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AIDDISON: Empowering Drug Discovery with AI/ML and CADD Tools in a Secure, Web-Based SaaS Platform
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Journal of Chemical Information and Modeling

Cite this: J. Chem. Inf. Model. 2024, 64, 1, 3–8
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https://doi.org/10.1021/acs.jcim.3c01016
Published December 22, 2023

Copyright © 2023 The Authors. Published by American Chemical Society. This publication is licensed under

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Abstract

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The widespread proliferation of artificial intelligence (AI) and machine learning (ML) methods has a profound effect on the drug discovery process. However, many scientists are reluctant to utilize these powerful tools due to the steep learning curve typically associated with them. AIDDISON offers a convenient, secure, web-based platform for drug discovery, addressing the reluctance of scientists to adopt AI and ML methods due to the steep learning curve. By seamlessly integrating generative models, ADMET property predictions, searches in vast chemical spaces, and molecular docking, AIDDISON provides a sophisticated platform for modern drug discovery. It enables less computer-savvy scientists to utilize these powerful tools in their daily activities, as demonstrated by an example of identifying a valuable set of molecules for lead optimization. With AIDDISON, the benefits of AI/ML in drug discovery are accessible to all.

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Introduction

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The widespread popularity and use of machine learning (ML) and artificial intelligence (AI)-based methods has increased dramatically during the past decade. Applications of AI in the life sciences and specifically chemistry have seen an exponential increase in research publications since 2015. (1) Some of the most promising areas deal with the prediction of bioactivity of novel molecules, (2) generation of 3D protein structures from sequence data, (3) calculation of a variety of ADME/Tox properties, (4) as well as suggestions of synthetic routes to complex target molecules. (5) Simultaneously, advances in virtual screening have made efficient sampling of vast chemical spaces (i.e., billions of molecules) possible, (6) thus providing a rich source of novel and, equally important, synthesizable molecules for evaluation in ML models or docking experiments. (7) Unfortunately, many of the recent advances are often too difficult for casual users to master since they are often deployed without a convenient and intuitive interface.
AIDDISON, an AI-powered drug discovery platform, was developed to address the need to accelerate hit identification and lead optimization in the drug discovery process by tapping into an underutilized resource─medicinal chemists themselves. Through seamless integration, AIDDISON harnesses the power of both computer-aided drug design (CADD) tools and AI to virtually screen for or generate novel molecules. As depicted in Figure 1, AIDDISON can be used to identify or generate thousands of viable molecules as the starting point in an analysis. These can come from a variety of sources─2D similarity searches of public databases, 2D pharmacophore searches of virtual chemical collections, de novo molecule design using generative models, and, of course, direct user input. Property-based filtering is a critical step in the process since it can be used to select those molecules to advance with the highest probability of success. (8) Docking experiments or shape-based alignment to a known active ligand is then used to evaluate potential biological activity. Finally, the best molecular designs can be sent to SYNTHIA retrosynthesis software (5) to assess their synthesizability and identify necessary reagents. Employing AIDDISON should enable scientists to accelerate the drug discovery process and identify novel hits faster and with better property profiles that will cause fewer failures in subsequent lead optimization and development stages. AIDDISON is based on ongoing research and active development, and a variety of functionalities are planned to be implemented in the next releases. As part of the security requirements, AIDDISON complies with ISO 27001 standards, the certificate for the highest level of information security for a digital product.

Figure 1

Figure 1. Workflows implemented in AIDDISON.

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Methods

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AIDDISON was developed as a secure software as a service (SaaS) environment (following ISO 27001 standards (9)). It utilizes a cloud-based, serverless architecture, which allows companies to keep computational costs under control while giving access to proven AI as well as commercial computational technologies to end-users. All workflows are driven from a common interface, and results are displayed in a convenient, readily digestible manner.

2D Similarity Search

FPSim2 (10) is used to rapidly perform chemical similarity search of a given target molecule on large collections of compounds that have either been reported or are commercially available. Structural features (ECFP2) are encoded into molecular fingerprints (bitstrings) for comparison. Tanimoto similarity is then computed to the target structure. Those molecules whose similarity is above a desired threshold are returned. Currently, the available searchable collections include the Sigma-Aldrich catalog, PubChem, (11) ChEMBL, (12) and ZINC. (13) Using the same search method across all databases standardizes the results.

2D Pharmacophore Search

The 2D pharmacophore search computes similarity to a target molecule by comparing the similarity of Feature Trees (FTrees) as implemented by BioSolveIT. (14,15) This is a highly efficient and effective tool for scaffold hopping and ligand-based screening of incredibly vast virtual chemical space. Its underlying topological descriptors capture ring/chain and pharmacophore attributes; the relationships among these descriptors are kept intact using a reduced graph representation, thus allowing for extremely rapid comparisons.
During the past few years, the number of available screening compounds has grown larger than ever before, through both physical and virtual libraries. Billions of synthetically accessible compounds are offered by companies like Enamine (REAL space) (16) and WuXi (GalaXi). (17) In addition to these virtual collections, SA-Space is a synthetically accessible, ultra-large virtual chemical space generated from Sigma-Aldrich building block chemicals and well-known robust chemical transformation rules. SA-Space encompasses approximately 25 billion virtual compounds which can be searched quickly and exclusively via AIDDISON. The upcoming release of AIDDISON enables customized virtual chemical spaces based on user-supplied reactions and reagents, which can be explored using the same FTrees search algorithm.

De Novo Design (Generative Models)

Recent interest in generative AI models for ligand-based de novo drug design has significantly increased. Within AIDDISON, de novo design based upon REINVENT 2.0 (18) generates a set of virtual molecules with desired chemical properties from a target molecule of interest and a desired level of chemical diversity sampled. The reward function for the reinforcement learning is composed of terms such as druglikeness (QED) (19) and similarity to target structure (using FTrees). An additional term is used for the assessment of synthetic accessibility via a connection to SYNTHIA retrosynthesis software. (5) We are working on extending the scoring components by user-defined models. Molecules with optimal scores are returned for further analysis. Results are evaluated, and a subset of the best are docked for evaluation of potential binding affinity.

Shape-Based Search

Shape-based search, based on Cresset’s Flare, (20) is an effective method for evaluating novel molecules via their 3D alignment to a target molecule. Once the crystal structure or low-energy conformer has been determined for the target, property-based field points are generated for it. These field point patterns, combined with their shape, are used to align and score a “database” of molecules against a reference which is usually a known active. An example is provided in Figure 2. In this context, the default Dice similarity has worked well and provided meaningful results. The Gallery View is then used to visualize the 3D structural alignment results. Alternatively, using the asymmetric Tversky index, a user can specify whether a subfield (akin to a substructure) or superfield search is performed. For example, these can be useful in determining whether a novel bioisosteric fragment is found in a larger target molecule. Another practical use is to reduce the number of molecules sent to molecular docking by a priori filtering out molecules that do not align well to a reference ligand. Figure 2 illustrates the 3D shape alignment of XAV-939 against the bioactive conformation of the ligand Olaparib. (21)

Figure 2

Figure 2. Shape-based alignment of XAV-939 against the crystal-bound conformation of Olaparib.

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Molecular Docking

Protein structures are necessary to initiate the Molecular Docking workflow. They can be easily added to a company’s private protein collection directly through an API to the PDB (22) and an appropriate PDB accession code. Alternatively, a user can directly upload a protein structure (in PDB format) from their own system. Druggable pockets can be identified either algorithmically, by manual specification, or from the pocket surrounding the crystal-bound ligand. (23)
Accurate modeling of protein–ligand interactions is essential for successful docking experiments. The Molecular Docking workflow, based upon Flare Docking from Cresset, (24) is used to evaluate molecules in the binding pocket or active site of a protein. Upon selection of the target protein structure and an indication of the binding pocket (by choosing a reference ligand or pocket), hydrogens and charges are automatically added to amino acid residues (via Cresset tools). Multiple low-energy conformers are generated for the set of molecules that will be docked. The optimal pose is identified using LF RankScore which is an energy function specifically tuned to achieve a pose similar to the reported crystal ligand and then returned to the user.
Results can be visualized in a Gallery View, where the new molecules are displayed inside the chosen pocket as shown in Figure 3. The solvent-accessible surface of the protein and the reference ligand can be displayed as well. The user can thus see how each molecule “fits” in the pocket relative to the crystal structure. This also allows the user to assess the binding mode and which protein–ligand interactions are formed. A Table View gives the user a chance to sort by various computed quantities, such as VSScore (virtual screen score), which provides an indication of potential bioactivity, and a calculated docking score called “Binding Free Energy” (dG) from the Flare software. It should be noted that this is not the free energy of binding one obtains from Free Energy Perturbation (FEP) calculations. This term is comprised of the force field energy terms (enthalpy) and an estimated entropy of binding for the protein–ligand complex. Combined with calculated physicochemical properties, these energy-based parameters help to select the “best” candidates to pursue.

Figure 3

Figure 3. Visualization of results from Molecular Docking workflow.

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Results

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Case Study. Tankyrase Inhibitors

β-Catenin is a dual function protein involved in the regulation and coordination of cell–cell adhesion, gene transcription, and overall physiological homeostasis. (25) Mutations and overexpression of β-catenin are associated with many cancers, including hepatocellular carcinoma, (26) colorectal carcinoma, (27) lung cancer, (28) malignant breast tumors, (29) and ovarian and endometrial cancer. (30) Though Wnt is the chief regulator of β-catenin, cellular levels are influenced by the β-catenin destruction complex (APC/GSK/CK1/Axin) which marks the protein (via phosphorylation and ubiquitination) for degradation by the proteasome. Tankyrase, on the other hand, is used by the cell to remove Axin which is a component of this complex. This limits the levels of β-catenin destruction complex and thus increases the amount of cellular β-catenin. Therefore, effectively blocking tankyrase facilitates β-catenin removal which leads to anticancer activity of tankyrase inhibitors. (31)
The challenge of discovering potentially novel tankyrase inhibitors is intriguing since many potent molecules with a variety of scaffolds are known. (32,33) Starting from a known tankyrase inhibitor, XAV-939 (4) (34) as the target, de novo design led to the identification of several different scaffolds which could ultimately prove to be useful. The well-known quinazoline-4(3H)-one scaffold (5) was chosen to exemplify the process. Two-dimensional similarity and pharmacophore search were used to identify a set of similar structures to construct an SAR around. The workflow is illustrated in Figure 4, where the retrosynthetic pathways were provided by SYNTHIA software. (5) All molecules were docked using the crystal structure of XAV-939 bound to tankyrase 2 (PDBID: 3KR8). (35) Interestingly, a known tankyrase inhibitor from ChEMBL, flavones, was identified as well from de novo design. (36,37) These are shown in Table 1. In total, 14k compounds were generated using de novo design (2k per each of the four diversity filters based on Bemis–Murcko and topological scaffolds) and 2D pharmacophore search (6k over the three virtual chemical spaces).

Figure 4

Figure 4. Case study: design and refinement of tankyrase inhibitors.

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Table 1. Known Tankyase Inhibitor Class (Flavones) in ChEMBL Identified from De Novo Design Starting from the Target Structure XAV-939 (4)

Discussion

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In the example provided, the process started with de novo design utilizing known active molecules as targets; a tankyrase inhibitor XAV-939 was used as the starting point to generate a new series of inhibitors based on the quinazoline-4(3H)-one scaffold.
The chemical space around XAV-939 (tankyrase inhibitor) was thoroughly explored by using all options of de novo molecule design and against all virtual compound collections. The results were first exported from AIDDISON and then uploaded and displayed by the Chemplot’s UMAP option, (38) as shown in Figure 5. They were grouped according to structural as well as method “similarity”. The green points represent molecules that came from de novo molecular design while the orange points show the distribution of molecules that result from 2D pharmacophore search of virtual chemical space. The encircled region represents the quinazoline-one (5) from de novo design; it led to the identification of a set of similar molecules from 2D pharmacophore search which are predicted to be active. The distribution of both sets of molecules is reminiscent of what was illustrated by Meyers et al. (2) when discussing generative models. That is, generative models thoroughly explore one region of chemical space while virtual collections sample chemical space more broadly.

Figure 5

Figure 5. Chemical space explored around XAV-939 using de novo design (green) and 2D pharmacophore search (gold) of virtual collections.

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It should be noted that these analyses do not have to be “one and done” in that the methods themselves are robust enough to restart with different target molecules and run multiple times if desired. The importance of screening chemical space with different methods should not be underestimated since one should not expect to find high-quality results from a single method alone. Rather, these tools are complementary, and when used in conjunction with property-based filtering of hit sets in AIDDISON, they can produce a small set of interesting molecules for synthesis and further testing.
As a note, all licenses to run commercial applications within AIDDISON are included. No additional licenses are required.

Summary

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AIDDISON is a secure, web-based SaaS drug discovery engine that combines the power of AI/ML and CADD tools in a seamless fashion. Less computationally sophisticated users can now benefit from the powerful ligand- and structure-based design tools to rapidly identify novel, potentially active molecules which have good predicted ADMET profiles and are synthetically accessible. A use case example for lead optimization was provided. The example illustrated how easy it is to generate a set of molecules for SAR analysis and lead optimization around an alternative scaffold. Reported inhibitors of tankyrase in ChEMBL were identified as well. This use-case scenario exemplifies AIDDISON capabilities and the way idea generation workflows can be used in a complementary fashion; this is an advantage AIDDISON offers.

Data Availability

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The AIDDISON platform is commercially available to the public (https://www.sigmaaldrich.com/US/en/services/software-and-digital-platforms/aiddison-ai-powered-drug-discovery). The platform incorporates REINVENT 3.2 which is publicly available from https://github.com/MolecularAI/Reinvent. The generative model is pretrained and publicly accessible from https://github.com/MolecularAI/ReinventCommunity/tree/master/notebooks/models as “random.prior.new”. The third-party software included in AIDDISON are the FTrees algorithm (v6.10) from BioSolveIT (https://www.biosolveit.de/products/#FTrees), Flare (v7.2) and pyFlare (v7) from Cresset (https://www.cresset-group.com/software/flare), and Synthia (v23.2) from MilliporeSigma, the U.S. and Canada Life Science business of Merck KGaA, Darmstadt, Germany (https://www.synthiaonline.com). All physicochemical properties and the clustering algorithms were implemented using RDKit (https://github.com/rdkit/rdkit). The starting molecules, the resulting compounds, and the parameters to run the workflows in the case study are shared at Zenodo (https://zenodo.org/record/10231008).

Author Information

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  • Corresponding Authors
    • Daniel Kuhn - Merck Healthcare KGaA, Medicinal Chemistry and Drug Design, Darmstadt 64293, Germany;  Email: [email protected]
    • Ashwini Ghogare - MilliporeSigma, 400 Summit Drive, Burlington, Massachusetts 01803, United States;  Email: [email protected]
  • Authors
    • Andrew Rusinko - MilliporeSigma, 400 Summit Drive, Burlington, Massachusetts 01803, United States
    • Mohammad Rezaei - MilliporeSigma, 400 Summit Drive, Burlington, Massachusetts 01803, United States;  Orcidhttps://orcid.org/0000-0001-5039-2717
    • Lukas Friedrich - Merck Healthcare KGaA, Medicinal Chemistry and Drug Design, Darmstadt 64293, Germany
    • Hans-Peter Buchstaller - Merck Healthcare KGaA, Medicinal Chemistry and Drug Design, Darmstadt 64293, Germany;  Orcidhttps://orcid.org/0000-0002-0577-8319
  • Notes
    The authors declare no competing financial interest.

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    Mendez, D.; Gaulton, A.; Bento, A. P.; Chambers, J.; De Veij, M.; Félix, E.; Magariños, M. P.; Mosquera, J. F.; Mutowo, P.; Nowotka, M.; Gordillo-Marañón, M.; Hunter, F.; Junco, L.; Mugumbate, G.; Rodriguez-Lopez, M.; Atkinson, F.; Bosc, N.; Radoux, C. J.; Segura-Cabrera, A.; Leach, A. R.; Hersey, A. ChEMBL: Towards Direct Deposition of Bioassay Data. Nucleic Acids Res. 2019, 47 (D1), D930– D940,  DOI: 10.1093/nar/gky1075
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    ChEMBL: towards direct deposition of bioassay data
    Mendez, David; Gaulton, Anna; Bento, A. Patricia; Chambers, Jon; De Veij, Marleen; Felix, Eloy; Magarinos, Maria Paula; Mosquera, Juan F.; Mutowo, Prudence; Nowotka, Michal; Gordillo-Maranon, Maria; Hunter, Fiona; Junco, Laura; Mugumbate, Grace; Rodriguez-Lopez, Milagros; Atkinson, Francis; Bosc, Nicolas; Radoux, Chris J.; Cabrera, Aldo Segura; Hersey, Anne; Leach, Andrew R.
    Nucleic Acids Research (2019), 47 (D1), D930-D940CODEN: NARHAD; ISSN:1362-4962. (Oxford University Press)
    ChEMBL is a large, open-access bioactivity database, previously described in the 2012, 2014 and 2017 Nucleic Acids Research Database Issues. In the last two years, several important improvements have been made to the database and are described here. These include more robust capture and representation of assay details; a new data deposition system, allowing updating of data sets and deposition of supplementary data; and a completely redesigned web interface, with enhanced search and filtering capabilities.
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    Irwin, J. J.; Tang, K. G.; Young, J.; Dandarchuluun, C.; Wong, B. R.; Khurelbaatar, M.; Moroz, Y. S.; Mayfield, J.; Sayle, R. A. ZINC20-A Free Ultralarge-Scale Chemical Database for Ligand Discovery. J. Chem. Inf. Model. 2020, 60 (12), 6065– 6073,  DOI: 10.1021/acs.jcim.0c00675
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    ZINC20-A Free Ultralarge-Scale Chemical Database for Ligand Discovery
    Irwin, John J.; Tang, Khanh G.; Young, Jennifer; Dandarchuluun, Chinzorig; Wong, Benjamin R.; Khurelbaatar, Munkhzul; Moroz, Yurii S.; Mayfield, John; Sayle, Roger A.
    Journal of Chemical Information and Modeling (2020), 60 (12), 6065-6073CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
    Identifying and purchasing new small mols. to test in biol. assays are enabling for ligand discovery, but as purchasable chem. space continues to grow into the tens of billions based on inexpensive make-on-demand compds., simply searching this space becomes a major challenge. We have therefore developed ZINC20, a new version of ZINC with two major new features: billions of new mols. and new methods to search them. As a fully enumerated database, ZINC can be searched precisely using explicit at.-level graph-based methods, such as SmallWorld for similarity and Arthor for pattern and substructure search, as well as 3D methods such as docking. Anal. of the new make-on-demand compd. sets by these and related tools reveals startling features. For instance, over 97% of the core Bemis-Murcko scaffolds in make-on-demand libraries are unavailable from "in-stock" collections. Correspondingly, the no. of new Bemis-Murcko scaffolds is rising almost as a linear fraction of the elaborated mols. Thus, an 88-fold increase in the no. of mols. in the make-on-demand vs. the in-stock sets is built upon a 16-fold increase in the no. of Bemis-Murcko scaffolds. The make-on-demand library is also more structurally diverse than phys. libraries, with a massive increase in disk- and sphere-like shaped mols. The new system is freely available at zinc20.docking.org.
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    Rarey, M.; Dixon, J. S. Feature Trees: A New Molecular Similarity Measure Based on Tree Matching. J. Comput. Aided. Mol. Des. 1998, 12, 471– 490,  DOI: 10.1023/A:1008068904628
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    Feature trees: a new molecular similarity measure based on tree matching
    Rarey, Matthias; Dixon, J. Scott
    Journal of Computer-Aided Molecular Design (1998), 12 (5), 471-490CODEN: JCADEQ; ISSN:0920-654X. (Kluwer Academic Publishers)
    In this paper we present a new method for evaluating mol. similarity between small org. compds. Instead of a linear representation like fingerprints, a more complex description, a feature tree, is calcd. for a mol. A feature tree represents hydrophobic fragments and functional groups of the mol. and the way these groups are linked together. Each node in the tree is labeled with a set of features representing chem. properties of the part of the mol. corresponding to the node. The comparison of feature trees is based on matching subtrees of two feature trees onto each other. Two algorithms for tackling the matching problem are described throughout this paper. On a dataset of about 1000 mols., we demonstrate the ability of our approach to identify mols. belonging to the same class of inhibitors. With a second dataset of 58 mols. with known binding modes taken from the Brookhaven Protein Data Bank, we show that the matchings produced by our algorithms are compatible with the relative orientation of the mols. in the active site in 61% of the test cases. The av. computation time for a pair comparison is about 50 ms on a current workstation.
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    Boehm, M.; Wu, T.-Y.; Claussen, H.; Lemmen, C. Similarity Searching and Scaffold Hopping in Synthetically Accessible Combinatorial Chemistry Spaces. J. Med. Chem. 2008, 51, 2468– 2480,  DOI: 10.1021/jm0707727
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    Similarity searching and scaffold hopping in synthetically accessible combinatorial chemistry spaces
    Boehm, Markus; Wu, Tong-Ying; Claussen, Holger; Lemmen, Christian
    Journal of Medicinal Chemistry (2008), 51 (8), 2468-2480CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Large collections of combinatorial libraries are an integral element in today's pharmaceutical industry. It is of great interest to perform similarity searches against all virtual compds. that are synthetically accessible by any such library. Here we describe the successful application of a new software tool CoLibri on 358 combinatorial libraries based on validated reaction protocols to create a single chem. space contg. over 1012 possible products. Similarity searching with FTrees-FS allows the systematic exploration of this space without the need to enumerate all product structures. The search result is a set of virtual hits which are synthetically accessible by one or more of the existing reaction protocols. Grouping these virtual hits by their synthetic protocols allows the rapid design and synthesis of multiple follow-up libraries. Such library ideas support hit-to-lead design efforts for tasks like follow-up from high-throughput screening hits or scaffold hopping from one hit to another attractive series.
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    Blaschke, T.; Arús-Pous, J.; Chen, H.; Margreitter, C.; Tyrchan, C.; Engkvist, O.; Papadopoulos, K.; Patronov, A. REINVENT 2.0: An AI Tool for De Novo Drug Design. J. Chem. Inf. Model. 2020, 60 (12), 5918– 5922,  DOI: 10.1021/acs.jcim.0c00915
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    REINVENT 2.0: An AI Tool for De Novo Drug Design
    Blaschke, Thomas; Arus-Pous, Josep; Chen, Hongming; Margreitter, Christian; Tyrchan, Christian; Engkvist, Ola; Papadopoulos, Kostas; Patronov, Atanas
    Journal of Chemical Information and Modeling (2020), 60 (12), 5918-5922CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
    In the past few years, we have witnessed a renaissance of the field of mol. de novo drug design. The advancements in deep learning and artificial intelligence (AI) have triggered an avalanche of ideas on how to translate such techniques to a variety of domains including the field of drug design. A range of architectures have been devised to find the optimal way of generating chem. compds. by using either graph- or string (SMILES)-based representations. With this application note, we aim to offer the community a prodn.-ready tool for de novo design, called REINVENT. It can be effectively applied on drug discovery projects that are striving to resolve either exploration or exploitation problems while navigating the chem. space. It can facilitate the idea generation process by bringing to the researcher's attention the most promising compds. REINVENT's code is publicly available at https://github.com/MolecularAI/Reinvent.
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    Bickerton, G. R.; Paolini, G. V.; Besnard, J.; Muresan, S.; Hopkins, A. L. Quantifying the Chemical Beauty of Drugs. Nat. Chem. 2012, 4, 90– 98,  DOI: 10.1038/nchem.1243
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    Quantifying the chemical beauty of drugs
    Bickerton, G. Richard; Paolini, Gaia V.; Besnard, Jeremy; Muresan, Sorel; Hopkins, Andrew L.
    Nature Chemistry (2012), 4 (2), 90-98CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
    Drug-likeness is a key consideration when selecting compds. during the early stages of drug discovery. However, evaluation of drug-likeness in abs. terms does not reflect adequately the whole spectrum of compd. quality. More worryingly, widely used rules may inadvertently foster undesirable mol. property inflation as they permit the encroachment of rule-compliant compds. towards their boundaries. We propose a measure of drug-likeness based on the concept of desirability called the quant. est. of drug-likeness (QED). The empirical rationale of QED reflects the underlying distribution of mol. properties. QED is intuitive, transparent, straightforward to implement in many practical settings and allows compds. to be ranked by their relative merit. We extended the utility of QED by applying it to the problem of mol. target druggability assessment by prioritizing a large set of published bioactive compds. The measure may also capture the abstr. notion of aesthetics in medicinal chem.
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    Narwal, M.; Venkannagari, H.; Lehtiö, L. Structural Basis of Selective Inhibition of Human Tankyrases. J. Med. Chem. 2012, 55 (3), 1360– 1367,  DOI: 10.1021/jm201510p
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    Structural Basis of Selective Inhibition of Human Tankyrases
    Narwal, Mohit; Venkannagari, Harikanth; Lehtio, Lari
    Journal of Medicinal Chemistry (2012), 55 (3), 1360-1367CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Tankyrases are poly(ADP-ribose) polymerases that have many cellular functions. They play pharmaceutically important roles, at least in telomere homeostasis and Wnt signaling, by covalently ADP-ribosylating target proteins and consequently regulating their functions. These features make tankyrases potential targets for treatment of cancer. We report here crystal structures of human tankyrase 2 catalytic fragment in complex with a byproduct, nicotinamide, and with selective inhibitors of tankyrases (IWR-1) and PARPs 1 and 2 (olaparib). Binding of these inhibitors to tankyrase 2 induces specific conformational changes. The crystal structures explain the selectivity of the inhibitors, reveal the flexibility of a substrate binding loop, and explain existing structure-activity relationship data. The first crystal structure of a PARP enzyme in complex with a potent inhibitor, IWR-1, that does not bind to the widely utilized nicotinamide-binding site makes the structure valuable for development of PARP inhibitors in general.
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    Berman, H. M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T. N.; Weissig, H.; Shindyalov, I. N.; Bourne, P. E. The Protein Data Bank. Nucleic Acids Res. 2000, 28, 235– 242,  DOI: 10.1093/nar/28.1.235
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    The Protein Data Bank
    Berman, Helen M.; Westbrook, John; Feng, Zukang; Gilliland, Gary; Bhat, T. N.; Weissig, Helge; Shindyalov, Ilya N.; Bourne, Philip E.
    Nucleic Acids Research (2000), 28 (1), 235-242CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
    The Protein Data Bank (PDB; http://www.rcsb.org/pdb/)is the single worldwide archive of structural data of biol. macromols. This paper describes the goals of the PDB, the systems in place for data deposition and access, how to obtain further information, and near-term plans for the future development of the resource.
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    Volkamer, A.; Kuhn, D.; Rippmann, F.; Rarey, M. DoGSiteScorer: A Web Server for Automatic Binding Site Prediction, Analysis and Druggability Assessment, Analysis and Druggability Assessment. Bioinformatics 2012, 28 (15), 2074– 5,  DOI: 10.1093/bioinformatics/bts310
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    DoGSiteScorer: a web server for automatic binding site prediction, analysis and druggability assessment
    Volkamer, Andrea; Kuhn, Daniel; Rippmann, Friedrich; Rarey, Matthias
    Bioinformatics (2012), 28 (15), 2074-2075CODEN: BOINFP; ISSN:1367-4803. (Oxford University Press)
    Motivation: Many drug discovery projects fail because the underlying target is finally found to be undruggable. Progress in structure elucidation of proteins now opens up a route to automatic structure-based target assessment. DoGSiteScorer is a newly developed automatic tool combining pocket prediction, characterization and druggability estn. and is now available through a web server. Availability: The DoGSiteScorer web server is freely available for academic use at http://dogsite.zbh.uni-hamburg.de Contact: [email protected].
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    Shang, S.; Hua, F.; Hu, A.-W. The Regulation of β-Catenin Activity and Function in Cancer: Therapeutic Opportunities. Oncotarget 2017, 8 (20), 33972– 33989,  DOI: 10.18632/oncotarget.15687
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    The regulation of β-catenin activity and function in cancer: therapeutic opportunities
    Shang Shuang; Hua Fang; Hu Zhuo-Wei
    Oncotarget (2017), 8 (20), 33972-33989 ISSN:.
    Wnt/β-catenin signaling is an evolutionarily conserved and versatile pathway that is known to be involved in embryonic development, tissue homeostasis and a wide variety of human diseases. Aberrant activation of this pathway gives rise to the accumulation of β-catenin in the nucleus and promotes the transcription of many oncogenes such as c-Myc and CyclinD-1. As a result, it contributes to carcinogenesis and tumor progression of several cancers, including colon cancer, hepatocellular carcinoma, pancreatic cancer, lung cancer and ovarian cancer. β-Catenin is a pivotal component of the Wnt signaling pathway and it is tightly regulated at three hierarchical levels: protein stability, subcellular localization and transcriptional activity. Uncovering the regulatory mechanisms of β-catenin will provide new insights into the pathogenesis of cancer and other diseases, as well as new therapeutic strategies against these diseases. In this review we dissect the concrete regulatory mechanisms of β-catenin from three aspects mentioned above. Then we focus on the role of β-catenin in cancer initiation, progression, dormancy, immunity and cancer stem cell maintenance. At last, we summarize the recent progress in the development of agents for the pharmacological modulation of β-catenin activity in cancer therapy.
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    Wong, C. M.; Fan, S. T.; Ng, I. O. beta-Catenin mutation and overexpression in hepatocellular carcinoma: clinicopathologic and prognostic significance. Cancer 2001, 92 (1), 136– 145,  DOI: 10.1002/1097-0142(20010701)92:1<136::AID-CNCR1301>3.0.CO;2-R
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    β-catenin mutation and overexpression in hepatocellular carcinoma: Clinicopathologic and prognostic significance
    Wong, Chun M.; Fan, Sheung T.; Ng, Irene O. L.
    Cancer (New York, NY, United States) (2001), 92 (1), 136-145CODEN: CANCAR; ISSN:0008-543X. (John Wiley & Sons, Inc.)
    β-Catenin has been recognized as a crit. member of the Wnt signaling pathway, and inappropriate activation of this pathway has been implicated in carcinogenesis. To det. the clin. significance of β-catenin in hepatocellular carcinoma (HCC), we performed mutational anal. at exon 3 of the gene, investigated the subcellular protein expression, and analyzed their clinicopathol. and prognostic significance in 60 patients with resected primary HCC. By direct DNA sequencing, somatic mutations of the β-catenin gene were detected in 7 (12%) HCCs. All the mutations were found at the region (exon 3) responsible for phosphorylation and ubiquitination, therefore likely to result in stabilization of free cytoplasmic β-catenin. Nuclear accumulation of the β-catenin protein, similar to the response to the Wnt signal, was found in 10 (17%) HCCs and was closely assocd. with gene mutation (P < 0.001). In the remaining cases, nonnuclear type overexpression, i.e., overexpression in the cytoplasm and/or cytoplasmic membrane, was obsd. in 31 (62%) HCCs, thus suggesting that the mechanisms leading to β-catenin overexpression may be heterogeneous. HCCs with a nonnuclear type of β-catenin overexpression were more frequently larger than 5 cm in diam. (P = 0.022) and had poorer cellular differentiation (P = 0.037), and the patients had significantly shorter disease-free survival lengths (P = 0.041). Review of the data from previous studies in HCC showed that β-catenin mutations were more frequent in HCV-assocd. HCC than in HBV-assocd. ones. β-Catenin mutation and deregulation may play an important role in hepatocarcinogenesis. Nonnuclear type β-catenin overexpression appeared to have pathol. and prognostic significance.
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    Brabletz, T.; Jung, A.; Hermann, K.; Günther, K.; Hohenberger, W.; Kirchner, T. Nuclear overexpression of the oncoprotein beta-catenin in colorectal cancer is localized predominantly at the invasion front. Pathology, research and practice 1998, 194 (10), 701– 704,  DOI: 10.1016/S0344-0338(98)80129-5
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    Nuclear overexpression of the oncoprotein β-catenin in colorectal cancer is localized predominantly at the invasion front
    Brabletz, Thomas; Jung, Andreas; Hermann, Kathrin; Guenther, Klaus; Hohenberger, Werner; Kirchner, Thomas
    Pathology, Research and Practice (1998), 194 (10), 701-704CODEN: PARPDS; ISSN:0344-0338. (Gustav Fischer Verlag)
    The distribution of overexpressed β-catenin within individual colorectal carcinomas was investigated using immunohistochem. In the most tumors a strong nuclear expression of β-catenin was found, predominantly localized at the invasion front with strongest nuclear staining of isolated, scattered tumor cells. In contrast, cells in the tumor center often showed a membranous expression of β-catenin, comparable to normal colon epithelium. It is therefore likely, that in addn. to the overexpression of β-catenin caused by defects in the adenomatous polyposis coli (APC) locus, regulatory events in the tumor itself lead to a different distribution of this oncoprotein.
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    Shigemitsu, K.; Sekido, Y.; Usami, N.; Mori, S.; Sato, M.; Horio, Y.; Hasegawa, Y.; Bader, S.; Gazdar, A.; Minna, J.; Hida, T.; Yoshioka, H.; Imaizumi, M.; Ueda, Y.; Takahashi, M.; Shimokata, K. Genetic alteration of the beta-catenin gene (CTNNB1) in human lung cancer and malignant mesothelioma and identification of a new 3p21.3 homozygous deletion. Oncogene 2001, 20 (31), 4249– 4257,  DOI: 10.1038/sj.onc.1204557
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    Genetic alteration of the β-catenin gene (CTNNB1) in human lung cancer and malignant mesothelioma and identification of a new 3p21.3 homozygous deletion
    Shigemitsu, Kikuo; Sekido, Yoshitaka; Usami, Noriyasu; Mori, Shoichi; Sato, Mitsuo; Horio, Yoshitsugu; Hasegawa, Yoshinori; Bader, Scott A.; Gazdar, Adi F.; Minna, John D.; Hida, Toyoaki; Yoshioka, Hiromu; Imaizumi, Munehisa; Ueda, Yuichi; Takahashi, Masahide; Shimokata, Kaoru
    Oncogene (2001), 20 (31), 4249-4257CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)
    The β-catenin gene (CTNNB1) has been shown to be genetically mutated in various human malignancies. To det. whether the β-catenin gene is responsible for oncogenesis in thoracic malignancies, the authors searched for the mutation in 166 lung cancers (90 primary tumors and 76 cell lines), one blastoma and 10 malignant mesotheliomas (two primary tumors and eight cell lines). Among the lung cancers, including 43 small cell lung cancers (SCLCs) and 123 non-small cell lung cancers (NSCLCs), the authors identified four alterations in exon 3, which is the target region of mutation for stabilizing β-catenin. One primary adenocarcinoma had a somatic mutation from C to G, leading to an amino acid substitution from Ser to Cys at codon 37. Among the cell lines, SCLC NCI-H1092 had a mutation from A to G, leading to an Asp to Gly substitution at codon 6, NSCLC HCC15 had a mutation from C to T, leading to a Ser to Phe substitution at codon 45, and NSCLC NCI-H358 had a mutation from A to G, leading to a Thr to Ala substitution at codon 75. One blastoma also had a somatic mutation from C to G, leading to a Ser to Cys substitution at codon 37. Among the 10 malignant mesotheliomas, the authors identified a homozygous deletion in the NCI-H28 cell line. Cloning of the rearranged fragment from NCI-H28 indicated that all the exons except exon 1 of the β-catenin gene are deleted and that the deletion junction is 13 kb downstream from exon 1. Furthermore, Northern blot anal. of 26 lung cancer and eight mesothelioma cell line RNAs detected ubiquitous expression of the β-catenin messages except NCI-H28, although Western blot anal. showed that relatively less amts. of protein products were expressed in some of lung cancer cell lines. The authors' findings suggest that the β-catenin gene is infrequently mutated in lung cancer and that the NCI-H28 homozygous deletion of the β-catenin gene might indicate the possibility of a new tumor suppressor gene residing in this region at 3p21.3, where various types of human cancers show frequent allelic loss.
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    Li, K.; Pan, W.-T.; Ma, Y.-B.; Xu, X.-L.; Gao, Y.; He, Y.-Q.; Wei, L.; Zhang, J.-W. BMX activates Wnt/β-catenin signaling pathway to promote cell proliferation and migration in breast cancer. Breast Cancer 2020, 27 (3), 363– 371,  DOI: 10.1007/s12282-019-01024-8
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    BMX activates Wnt/β-catenin signaling pathway to promote cell proliferation and migration in breast cancer
    Li Kai; Pan Wen-Ting; Ma Yan-Bin; Xu Xiao-Long; Gao Yang; He Yan-Qi; Wei Lei; Zhang Jing-Wei
    Breast cancer (Tokyo, Japan) (2020), 27 (3), 363-371 ISSN:.
    BACKGROUND: Breast cancer has become a dangerous killer for the female, which seriously threatened women's life, leading to huge pressures to society. The present study assessed the mechanism underlying the involvement of bone marrow tyrosine kinase on chromosome X (BMX) in breast cancer development. METHODS: The expression of BMX was examined by qPCR and immunohistochemistry. The effect of BMX on cell proliferation and migration was detected by Clone formation assay and Transwell assay. In vitro study, the correlation of BMX with Wnt/β-catenin pathway was explored by western blot and TOP/FOP flash assay. RESULTS: In the present study, we found that BMX was up-regulated in breast cancer, which was associated with the tumor differentiation and TNM stage. Oncogenic BMX enhanced the ability of breast cancer cell proliferation and migration. Furthermore, BMX could up-regulate the protein expression levels of p-β-catenin (Y142), p-β-catenin(Y654) and inhibit the expression level of p-β-catenin (S33/37), thus activating Wnt/β-catenin pathway in MCF-7 and MDA-MB-231 cells. In addition, we revealed that BMX promoted GSK3β phosphorylation, which suppressed the degradation of β-catenin. CONCLUSIONS: In this study, we identified that BMX-activated Wnt/β-catenin signaling pathway, playing an oncogenic role in breast cancer, suggesting that BMX could become a potential treatment target of breast cancer.
  30. 30
    Zyla, R. E.; Olkhov-Mitsel, E.; Amemiya, Y.; Bassiouny, D.; Seth, A.; Djordjevic, B.; Nofech-Mozes, S.; Parra-Herran, C. CTNNB1Mutations and Aberrant β-Catenin Expression in Ovarian Endometrioid Carcinoma: Correlation With Patient Outcome. American journal of surgical pathology 2021, 45 (1), 68– 76,  DOI: 10.1097/PAS.0000000000001553
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    CTNNB1 Mutations and Aberrant β-Catenin Expression in Ovarian Endometrioid Carcinoma: Correlation With Patient Outcome
    Zyla Roman E; Seth Arun; Djordjevic Bojana; Nofech-Mozes Sharon; Parra-Herran Carlos; Zyla Roman E; Olkhov-Mitsel Ekaterina; Bassiouny Dina; Seth Arun; Djordjevic Bojana; Nofech-Mozes Sharon; Parra-Herran Carlos; Amemiya Yutaka; Seth Arun; Bassiouny Dina
    The American journal of surgical pathology (2021), 45 (1), 68-76 ISSN:.
    CTNNB1 mutations and aberrant β-catenin expression have adverse prognosis in endometrial endometrioid carcinoma, and recent evidence suggests a prognostic role of β-catenin in ovarian endometrioid carcinoma. Thus, we aimed to determine the prognostic value of the CTNNB1 mutational status, and its correlation with β-catenin expression, in a well-annotated cohort of 51 ovarian endometrioid carcinomas. We performed immunohistochemistry for β-catenin and developed an 11-gene next-generation sequencing panel that included whole exome sequencing of CTNNB1 and TP53. Results were correlated with clinicopathologic variables including disease-free and disease-specific survival. Tumor recurrence was documented in 14 patients (27%), and cancer-related death in 8 patients (16%). CTNNB1 mutations were found in 22 cases (43%), and nuclear β-catenin in 26 cases (51%). CTNNB1 mutation highly correlated with nuclear β-catenin (P<0.05). Mutated CTNNB1 status was statistically associated with better disease-free survival (P=0.04, log-rank test) and approached significance for better disease-specific survival (P=0.07). It also correlated with earlier International Federation of Gynecology and Obstetrics stage (P<0.05). Nuclear β-catenin, TP53 mutations, age, ProMisE group, surface involvement, tumor grade and stage also correlated with disease-free survival. There was no association between membranous β-catenin expression and disease-free or disease-specific survival. CTNNB1 mutations and nuclear β-catenin expression are associated with better progression-free survival in patients with OEC. This relationship may be in part due to a trend of CTNNB1-mutated tumors to present at early stage. β-catenin immunohistochemistry may serve as a prognostic biomarker and a surrogate for CTNN1B mutations in the evaluation of patients with ovarian endometrioid neoplasia, particularly those in reproductive-age or found incidentally without upfront staging surgery.
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    Ferri, M.; Liscio, P.; Carotti, A.; Asciutti, S.; Sardella, R.; Macchiarulo, A.; Camaioni, E. Targeting Wnt-driven Cancers: Discovery of Novel Tankyrase Inhibitors. Eur. J. Med. Chem. 2017, 142, 506– 522,  DOI: 10.1016/j.ejmech.2017.09.030
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    Targeting Wnt-driven cancers: Discovery of novel tankyrase inhibitors
    Ferri, Martina; Liscio, Paride; Carotti, Andrea; Asciutti, Stefania; Sardella, Roccaldo; Macchiarulo, Antonio; Camaioni, Emidio
    European Journal of Medicinal Chemistry (2017), 142 (), 506-522CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
    A review. Recent years have seen substantially heightened interest in the discovery of tankyrase inhibitors (TNKSi) as new promising anticancer agents. In this framework, the aim of this review article is focused on the description of potent TNKSi also endowed with disruptor activity toward the Wnt/β-catenin signaling pathway. Beginning with an overview of the most characterized TNKSi deriving from several drug design approaches and classifying them on the basis of the mol. interactions with the target, the authors discuss only those ones acting against Wnt cancer cell lines. In addn., comprehensive structure property relationships (SPR) emerging from the hit evolution processes and preclin. results are provided. The authors then review the most promising TNKSi hitherto reported in literature, acting in vivo models of Wnt-driven cancers. Some out-looks on current issues and future directions in this field are also discussed.
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    Buchstaller, H. P.; Anlauf, U.; Dorsch, D.; Kögler, S.; Kuhn, D.; Lehmann, M.; Leuthner, B.; Lodholz, S.; Musil, D.; Radtki, D.; Rettig, C.; Ritzert, C.; Rohdich, F.; Schneider, R.; Wegener, A.; Weigt, S.; Wilkinson, K.; Esdar, C. Optimization of a Screening Hit toward M2912, an Oral Tankyrase Inhibitor with Antitumor Activity in Colorectal Cancer Models. J. Med. Chem. 2021, 64 (14), 10371– 10392,  DOI: 10.1021/acs.jmedchem.1c00800
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    Optimization of a Screening Hit toward M2912, an Oral Tankyrase Inhibitor with Antitumor Activity in Colorectal Cancer Models
    Buchstaller, Hans-Peter; Anlauf, Uwe; Dorsch, Dieter; Koegler, Sarah; Kuhn, Daniel; Lehmann, Martin; Leuthner, Birgitta; Lodholz, Sara; Musil, Djordje; Radtki, Daniela; Rettig, Corinna; Ritzert, Claudio; Rohdich, Felix; Schneider, Richard; Wegener, Ansgar; Weigt, Stefan; Wilkinson, Kai; Esdar, Christina
    Journal of Medicinal Chemistry (2021), 64 (14), 10371-10392CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
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    Buchstaller, H. P.; Anlauf, U.; Dorsch, D.; Kuhn, D.; Lehmann, M.; Leuthner, B.; Musil, D.; Radtki, D.; Ritzert, C.; Rohdich, F.; Schneider, R.; Esdar, C. Discovery and Optimization of 2-Arylquinazolin-4-ones into a Potent and Selective Tankyrase Inhibitor Modulating Wnt Pathway Activity. J. Med. Chem. 2019, 62 (17), 7897– 7909,  DOI: 10.1021/acs.jmedchem.9b00656
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    Discovery and Optimization of 2-Arylquinazolin-4-ones into a Potent and Selective Tankyrase Inhibitor Modulating Wnt Pathway Activity
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    Tankyrases 1 and 2 (TNKS1/2) are promising pharmacol. targets which recently gained interest for anticancer therapy in Wnt pathway dependent tumors. 2-Aryl-quinazolinones were identified and optimized into potent tankyrase inhibitors through SAR exploration around the quinazolinone core and the 4'-position of the Ph residue. These efforts were supported by anal. of TNKS X-ray and Watermap structures and resulted in compd. 5k(I), a potent, selective tankyrase inhibitor with favorable pharmacokinetic properties. The X-ray structure of I in complex with TNKS1 was solved and confirmed the design hypothesis. Modulation of Wnt pathway activity was demonstrated with this compd. in a colorectal xenograft model in vivo.
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    Mehta, C. C.; Bhatt, H. G. Tankyrase inhibitors as Antitumor Agents: a Patent Update (2013–2020). Expert Opinion on Therapeutic Patents 2021, 31 (7), 645– 661,  DOI: 10.1080/13543776.2021.1888929
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    Tankyrase inhibitors as antitumor agents: a patent update (2013 - 2020)
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    IntroductionTankyrase inhibitors gained significant attention as therapeutic targets in oncol. because of their potency. Their primary role in inhibiting the Wnt signaling pathway makes them an important class of compds. with the potential to be used as a combination therapy in future treatments of colorectal cancer. Areas coveredThis review describes pertinent work in the development of tankyrase inhibitors with a great emphasis on the recently patented TNKS inhibitors published from 2013 to 2020. This article also highlights a couple of promising candidates having tankyrase inhibitory effects and are currently undergoing clin. trials. Expert opinionFollowing the successful clin. applications of PARP inhibitors, tankyrase inhibition has gained significant attention in the research community as a target with high therapeutic potential. The ubiquitous role of tankyrase in cellular homeostasis and Wnt-dependent tumor proliferation brought difficulties for researchers to strike the right balance between potency and on-target toxicity. The need for novel tankyrase inhibitors with a better ADMET profile can introduce an addnl. regimen in treating various malignancies in monotherapy or adjuvant therapy. The development of combination therapies, including tankyrase inhibitors with or without PARP inhibitory properties, can potentially benefit the larger population of patients with unmet medical needs.
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    Karlberg, T.; Markova, N.; Johansson, I.; Hammarström, M.; Schütz, P.; Weigelt, J.; Schüler, H. Structural Basis for the Interaction between Tankyrase-2 and a Potent Wnt-Signaling Inhibitor. J. Med. Chem. 2010, 53 (14), 5352– 5355,  DOI: 10.1021/jm100249w
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    Structural Basis for the Interaction between Tankyrase-2 and a Potent Wnt-Signaling Inhibitor
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  • Abstract

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    Figure 1

    Figure 1. Workflows implemented in AIDDISON.

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    Figure 2

    Figure 2. Shape-based alignment of XAV-939 against the crystal-bound conformation of Olaparib.

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    Figure 3

    Figure 3. Visualization of results from Molecular Docking workflow.

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    Figure 4

    Figure 4. Case study: design and refinement of tankyrase inhibitors.

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    Figure 5

    Figure 5. Chemical space explored around XAV-939 using de novo design (green) and 2D pharmacophore search (gold) of virtual collections.

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      Mendez, David; Gaulton, Anna; Bento, A. Patricia; Chambers, Jon; De Veij, Marleen; Felix, Eloy; Magarinos, Maria Paula; Mosquera, Juan F.; Mutowo, Prudence; Nowotka, Michal; Gordillo-Maranon, Maria; Hunter, Fiona; Junco, Laura; Mugumbate, Grace; Rodriguez-Lopez, Milagros; Atkinson, Francis; Bosc, Nicolas; Radoux, Chris J.; Cabrera, Aldo Segura; Hersey, Anne; Leach, Andrew R.
      Nucleic Acids Research (2019), 47 (D1), D930-D940CODEN: NARHAD; ISSN:1362-4962. (Oxford University Press)
      ChEMBL is a large, open-access bioactivity database, previously described in the 2012, 2014 and 2017 Nucleic Acids Research Database Issues. In the last two years, several important improvements have been made to the database and are described here. These include more robust capture and representation of assay details; a new data deposition system, allowing updating of data sets and deposition of supplementary data; and a completely redesigned web interface, with enhanced search and filtering capabilities.
    13. 13
      Irwin, J. J.; Tang, K. G.; Young, J.; Dandarchuluun, C.; Wong, B. R.; Khurelbaatar, M.; Moroz, Y. S.; Mayfield, J.; Sayle, R. A. ZINC20-A Free Ultralarge-Scale Chemical Database for Ligand Discovery. J. Chem. Inf. Model. 2020, 60 (12), 6065– 6073,  DOI: 10.1021/acs.jcim.0c00675
      13
      ZINC20-A Free Ultralarge-Scale Chemical Database for Ligand Discovery
      Irwin, John J.; Tang, Khanh G.; Young, Jennifer; Dandarchuluun, Chinzorig; Wong, Benjamin R.; Khurelbaatar, Munkhzul; Moroz, Yurii S.; Mayfield, John; Sayle, Roger A.
      Journal of Chemical Information and Modeling (2020), 60 (12), 6065-6073CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
      Identifying and purchasing new small mols. to test in biol. assays are enabling for ligand discovery, but as purchasable chem. space continues to grow into the tens of billions based on inexpensive make-on-demand compds., simply searching this space becomes a major challenge. We have therefore developed ZINC20, a new version of ZINC with two major new features: billions of new mols. and new methods to search them. As a fully enumerated database, ZINC can be searched precisely using explicit at.-level graph-based methods, such as SmallWorld for similarity and Arthor for pattern and substructure search, as well as 3D methods such as docking. Anal. of the new make-on-demand compd. sets by these and related tools reveals startling features. For instance, over 97% of the core Bemis-Murcko scaffolds in make-on-demand libraries are unavailable from "in-stock" collections. Correspondingly, the no. of new Bemis-Murcko scaffolds is rising almost as a linear fraction of the elaborated mols. Thus, an 88-fold increase in the no. of mols. in the make-on-demand vs. the in-stock sets is built upon a 16-fold increase in the no. of Bemis-Murcko scaffolds. The make-on-demand library is also more structurally diverse than phys. libraries, with a massive increase in disk- and sphere-like shaped mols. The new system is freely available at zinc20.docking.org.
    14. 14
      Rarey, M.; Dixon, J. S. Feature Trees: A New Molecular Similarity Measure Based on Tree Matching. J. Comput. Aided. Mol. Des. 1998, 12, 471– 490,  DOI: 10.1023/A:1008068904628
      16
      Feature trees: a new molecular similarity measure based on tree matching
      Rarey, Matthias; Dixon, J. Scott
      Journal of Computer-Aided Molecular Design (1998), 12 (5), 471-490CODEN: JCADEQ; ISSN:0920-654X. (Kluwer Academic Publishers)
      In this paper we present a new method for evaluating mol. similarity between small org. compds. Instead of a linear representation like fingerprints, a more complex description, a feature tree, is calcd. for a mol. A feature tree represents hydrophobic fragments and functional groups of the mol. and the way these groups are linked together. Each node in the tree is labeled with a set of features representing chem. properties of the part of the mol. corresponding to the node. The comparison of feature trees is based on matching subtrees of two feature trees onto each other. Two algorithms for tackling the matching problem are described throughout this paper. On a dataset of about 1000 mols., we demonstrate the ability of our approach to identify mols. belonging to the same class of inhibitors. With a second dataset of 58 mols. with known binding modes taken from the Brookhaven Protein Data Bank, we show that the matchings produced by our algorithms are compatible with the relative orientation of the mols. in the active site in 61% of the test cases. The av. computation time for a pair comparison is about 50 ms on a current workstation.
    15. 15
      Boehm, M.; Wu, T.-Y.; Claussen, H.; Lemmen, C. Similarity Searching and Scaffold Hopping in Synthetically Accessible Combinatorial Chemistry Spaces. J. Med. Chem. 2008, 51, 2468– 2480,  DOI: 10.1021/jm0707727
      17
      Similarity searching and scaffold hopping in synthetically accessible combinatorial chemistry spaces
      Boehm, Markus; Wu, Tong-Ying; Claussen, Holger; Lemmen, Christian
      Journal of Medicinal Chemistry (2008), 51 (8), 2468-2480CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Large collections of combinatorial libraries are an integral element in today's pharmaceutical industry. It is of great interest to perform similarity searches against all virtual compds. that are synthetically accessible by any such library. Here we describe the successful application of a new software tool CoLibri on 358 combinatorial libraries based on validated reaction protocols to create a single chem. space contg. over 1012 possible products. Similarity searching with FTrees-FS allows the systematic exploration of this space without the need to enumerate all product structures. The search result is a set of virtual hits which are synthetically accessible by one or more of the existing reaction protocols. Grouping these virtual hits by their synthetic protocols allows the rapid design and synthesis of multiple follow-up libraries. Such library ideas support hit-to-lead design efforts for tasks like follow-up from high-throughput screening hits or scaffold hopping from one hit to another attractive series.
    16. 16
      Enamine REAL Space. https://enamine.net/compound-collections/real-compounds/real-space-navigator (accessed 2023-04–21).
      There is no corresponding record for this reference.
    17. 17
      WuXi GalaXi. https://wuxibiology.com/drug-discovery-services/hit-finding-and-screening-services/virtual-screening/ (accessed 2023-04–21).
      There is no corresponding record for this reference.
    18. 18
      Blaschke, T.; Arús-Pous, J.; Chen, H.; Margreitter, C.; Tyrchan, C.; Engkvist, O.; Papadopoulos, K.; Patronov, A. REINVENT 2.0: An AI Tool for De Novo Drug Design. J. Chem. Inf. Model. 2020, 60 (12), 5918– 5922,  DOI: 10.1021/acs.jcim.0c00915
      18
      REINVENT 2.0: An AI Tool for De Novo Drug Design
      Blaschke, Thomas; Arus-Pous, Josep; Chen, Hongming; Margreitter, Christian; Tyrchan, Christian; Engkvist, Ola; Papadopoulos, Kostas; Patronov, Atanas
      Journal of Chemical Information and Modeling (2020), 60 (12), 5918-5922CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
      In the past few years, we have witnessed a renaissance of the field of mol. de novo drug design. The advancements in deep learning and artificial intelligence (AI) have triggered an avalanche of ideas on how to translate such techniques to a variety of domains including the field of drug design. A range of architectures have been devised to find the optimal way of generating chem. compds. by using either graph- or string (SMILES)-based representations. With this application note, we aim to offer the community a prodn.-ready tool for de novo design, called REINVENT. It can be effectively applied on drug discovery projects that are striving to resolve either exploration or exploitation problems while navigating the chem. space. It can facilitate the idea generation process by bringing to the researcher's attention the most promising compds. REINVENT's code is publicly available at https://github.com/MolecularAI/Reinvent.
    19. 19
      Bickerton, G. R.; Paolini, G. V.; Besnard, J.; Muresan, S.; Hopkins, A. L. Quantifying the Chemical Beauty of Drugs. Nat. Chem. 2012, 4, 90– 98,  DOI: 10.1038/nchem.1243
      19
      Quantifying the chemical beauty of drugs
      Bickerton, G. Richard; Paolini, Gaia V.; Besnard, Jeremy; Muresan, Sorel; Hopkins, Andrew L.
      Nature Chemistry (2012), 4 (2), 90-98CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
      Drug-likeness is a key consideration when selecting compds. during the early stages of drug discovery. However, evaluation of drug-likeness in abs. terms does not reflect adequately the whole spectrum of compd. quality. More worryingly, widely used rules may inadvertently foster undesirable mol. property inflation as they permit the encroachment of rule-compliant compds. towards their boundaries. We propose a measure of drug-likeness based on the concept of desirability called the quant. est. of drug-likeness (QED). The empirical rationale of QED reflects the underlying distribution of mol. properties. QED is intuitive, transparent, straightforward to implement in many practical settings and allows compds. to be ranked by their relative merit. We extended the utility of QED by applying it to the problem of mol. target druggability assessment by prioritizing a large set of published bioactive compds. The measure may also capture the abstr. notion of aesthetics in medicinal chem.
    20. 20
      Cheeseright, T. Fragment hopping with Blaze. Shape Match 2022 (accessed 2023–04–26).
      There is no corresponding record for this reference.
    21. 21
      Narwal, M.; Venkannagari, H.; Lehtiö, L. Structural Basis of Selective Inhibition of Human Tankyrases. J. Med. Chem. 2012, 55 (3), 1360– 1367,  DOI: 10.1021/jm201510p
      21
      Structural Basis of Selective Inhibition of Human Tankyrases
      Narwal, Mohit; Venkannagari, Harikanth; Lehtio, Lari
      Journal of Medicinal Chemistry (2012), 55 (3), 1360-1367CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Tankyrases are poly(ADP-ribose) polymerases that have many cellular functions. They play pharmaceutically important roles, at least in telomere homeostasis and Wnt signaling, by covalently ADP-ribosylating target proteins and consequently regulating their functions. These features make tankyrases potential targets for treatment of cancer. We report here crystal structures of human tankyrase 2 catalytic fragment in complex with a byproduct, nicotinamide, and with selective inhibitors of tankyrases (IWR-1) and PARPs 1 and 2 (olaparib). Binding of these inhibitors to tankyrase 2 induces specific conformational changes. The crystal structures explain the selectivity of the inhibitors, reveal the flexibility of a substrate binding loop, and explain existing structure-activity relationship data. The first crystal structure of a PARP enzyme in complex with a potent inhibitor, IWR-1, that does not bind to the widely utilized nicotinamide-binding site makes the structure valuable for development of PARP inhibitors in general.
    22. 22
      Berman, H. M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T. N.; Weissig, H.; Shindyalov, I. N.; Bourne, P. E. The Protein Data Bank. Nucleic Acids Res. 2000, 28, 235– 242,  DOI: 10.1093/nar/28.1.235
      22
      The Protein Data Bank
      Berman, Helen M.; Westbrook, John; Feng, Zukang; Gilliland, Gary; Bhat, T. N.; Weissig, Helge; Shindyalov, Ilya N.; Bourne, Philip E.
      Nucleic Acids Research (2000), 28 (1), 235-242CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
      The Protein Data Bank (PDB; http://www.rcsb.org/pdb/)is the single worldwide archive of structural data of biol. macromols. This paper describes the goals of the PDB, the systems in place for data deposition and access, how to obtain further information, and near-term plans for the future development of the resource.
    23. 23
      Volkamer, A.; Kuhn, D.; Rippmann, F.; Rarey, M. DoGSiteScorer: A Web Server for Automatic Binding Site Prediction, Analysis and Druggability Assessment, Analysis and Druggability Assessment. Bioinformatics 2012, 28 (15), 2074– 5,  DOI: 10.1093/bioinformatics/bts310
      23
      DoGSiteScorer: a web server for automatic binding site prediction, analysis and druggability assessment
      Volkamer, Andrea; Kuhn, Daniel; Rippmann, Friedrich; Rarey, Matthias
      Bioinformatics (2012), 28 (15), 2074-2075CODEN: BOINFP; ISSN:1367-4803. (Oxford University Press)
      Motivation: Many drug discovery projects fail because the underlying target is finally found to be undruggable. Progress in structure elucidation of proteins now opens up a route to automatic structure-based target assessment. DoGSiteScorer is a newly developed automatic tool combining pocket prediction, characterization and druggability estn. and is now available through a web server. Availability: The DoGSiteScorer web server is freely available for academic use at http://dogsite.zbh.uni-hamburg.de Contact: [email protected].
    24. 24
      Cresset Flare Docking . 2022; https://www.cresset-group.com/software/flare-docking/ (accessed 2023–04–21).
      There is no corresponding record for this reference.
    25. 25
      Shang, S.; Hua, F.; Hu, A.-W. The Regulation of β-Catenin Activity and Function in Cancer: Therapeutic Opportunities. Oncotarget 2017, 8 (20), 33972– 33989,  DOI: 10.18632/oncotarget.15687
      25
      The regulation of β-catenin activity and function in cancer: therapeutic opportunities
      Shang Shuang; Hua Fang; Hu Zhuo-Wei
      Oncotarget (2017), 8 (20), 33972-33989 ISSN:.
      Wnt/β-catenin signaling is an evolutionarily conserved and versatile pathway that is known to be involved in embryonic development, tissue homeostasis and a wide variety of human diseases. Aberrant activation of this pathway gives rise to the accumulation of β-catenin in the nucleus and promotes the transcription of many oncogenes such as c-Myc and CyclinD-1. As a result, it contributes to carcinogenesis and tumor progression of several cancers, including colon cancer, hepatocellular carcinoma, pancreatic cancer, lung cancer and ovarian cancer. β-Catenin is a pivotal component of the Wnt signaling pathway and it is tightly regulated at three hierarchical levels: protein stability, subcellular localization and transcriptional activity. Uncovering the regulatory mechanisms of β-catenin will provide new insights into the pathogenesis of cancer and other diseases, as well as new therapeutic strategies against these diseases. In this review we dissect the concrete regulatory mechanisms of β-catenin from three aspects mentioned above. Then we focus on the role of β-catenin in cancer initiation, progression, dormancy, immunity and cancer stem cell maintenance. At last, we summarize the recent progress in the development of agents for the pharmacological modulation of β-catenin activity in cancer therapy.
    26. 26
      Wong, C. M.; Fan, S. T.; Ng, I. O. beta-Catenin mutation and overexpression in hepatocellular carcinoma: clinicopathologic and prognostic significance. Cancer 2001, 92 (1), 136– 145,  DOI: 10.1002/1097-0142(20010701)92:1<136::AID-CNCR1301>3.0.CO;2-R
      26
      β-catenin mutation and overexpression in hepatocellular carcinoma: Clinicopathologic and prognostic significance
      Wong, Chun M.; Fan, Sheung T.; Ng, Irene O. L.
      Cancer (New York, NY, United States) (2001), 92 (1), 136-145CODEN: CANCAR; ISSN:0008-543X. (John Wiley & Sons, Inc.)
      β-Catenin has been recognized as a crit. member of the Wnt signaling pathway, and inappropriate activation of this pathway has been implicated in carcinogenesis. To det. the clin. significance of β-catenin in hepatocellular carcinoma (HCC), we performed mutational anal. at exon 3 of the gene, investigated the subcellular protein expression, and analyzed their clinicopathol. and prognostic significance in 60 patients with resected primary HCC. By direct DNA sequencing, somatic mutations of the β-catenin gene were detected in 7 (12%) HCCs. All the mutations were found at the region (exon 3) responsible for phosphorylation and ubiquitination, therefore likely to result in stabilization of free cytoplasmic β-catenin. Nuclear accumulation of the β-catenin protein, similar to the response to the Wnt signal, was found in 10 (17%) HCCs and was closely assocd. with gene mutation (P < 0.001). In the remaining cases, nonnuclear type overexpression, i.e., overexpression in the cytoplasm and/or cytoplasmic membrane, was obsd. in 31 (62%) HCCs, thus suggesting that the mechanisms leading to β-catenin overexpression may be heterogeneous. HCCs with a nonnuclear type of β-catenin overexpression were more frequently larger than 5 cm in diam. (P = 0.022) and had poorer cellular differentiation (P = 0.037), and the patients had significantly shorter disease-free survival lengths (P = 0.041). Review of the data from previous studies in HCC showed that β-catenin mutations were more frequent in HCV-assocd. HCC than in HBV-assocd. ones. β-Catenin mutation and deregulation may play an important role in hepatocarcinogenesis. Nonnuclear type β-catenin overexpression appeared to have pathol. and prognostic significance.
    27. 27
      Brabletz, T.; Jung, A.; Hermann, K.; Günther, K.; Hohenberger, W.; Kirchner, T. Nuclear overexpression of the oncoprotein beta-catenin in colorectal cancer is localized predominantly at the invasion front. Pathology, research and practice 1998, 194 (10), 701– 704,  DOI: 10.1016/S0344-0338(98)80129-5
      27
      Nuclear overexpression of the oncoprotein β-catenin in colorectal cancer is localized predominantly at the invasion front
      Brabletz, Thomas; Jung, Andreas; Hermann, Kathrin; Guenther, Klaus; Hohenberger, Werner; Kirchner, Thomas
      Pathology, Research and Practice (1998), 194 (10), 701-704CODEN: PARPDS; ISSN:0344-0338. (Gustav Fischer Verlag)
      The distribution of overexpressed β-catenin within individual colorectal carcinomas was investigated using immunohistochem. In the most tumors a strong nuclear expression of β-catenin was found, predominantly localized at the invasion front with strongest nuclear staining of isolated, scattered tumor cells. In contrast, cells in the tumor center often showed a membranous expression of β-catenin, comparable to normal colon epithelium. It is therefore likely, that in addn. to the overexpression of β-catenin caused by defects in the adenomatous polyposis coli (APC) locus, regulatory events in the tumor itself lead to a different distribution of this oncoprotein.
    28. 28
      Shigemitsu, K.; Sekido, Y.; Usami, N.; Mori, S.; Sato, M.; Horio, Y.; Hasegawa, Y.; Bader, S.; Gazdar, A.; Minna, J.; Hida, T.; Yoshioka, H.; Imaizumi, M.; Ueda, Y.; Takahashi, M.; Shimokata, K. Genetic alteration of the beta-catenin gene (CTNNB1) in human lung cancer and malignant mesothelioma and identification of a new 3p21.3 homozygous deletion. Oncogene 2001, 20 (31), 4249– 4257,  DOI: 10.1038/sj.onc.1204557
      28
      Genetic alteration of the β-catenin gene (CTNNB1) in human lung cancer and malignant mesothelioma and identification of a new 3p21.3 homozygous deletion
      Shigemitsu, Kikuo; Sekido, Yoshitaka; Usami, Noriyasu; Mori, Shoichi; Sato, Mitsuo; Horio, Yoshitsugu; Hasegawa, Yoshinori; Bader, Scott A.; Gazdar, Adi F.; Minna, John D.; Hida, Toyoaki; Yoshioka, Hiromu; Imaizumi, Munehisa; Ueda, Yuichi; Takahashi, Masahide; Shimokata, Kaoru
      Oncogene (2001), 20 (31), 4249-4257CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)
      The β-catenin gene (CTNNB1) has been shown to be genetically mutated in various human malignancies. To det. whether the β-catenin gene is responsible for oncogenesis in thoracic malignancies, the authors searched for the mutation in 166 lung cancers (90 primary tumors and 76 cell lines), one blastoma and 10 malignant mesotheliomas (two primary tumors and eight cell lines). Among the lung cancers, including 43 small cell lung cancers (SCLCs) and 123 non-small cell lung cancers (NSCLCs), the authors identified four alterations in exon 3, which is the target region of mutation for stabilizing β-catenin. One primary adenocarcinoma had a somatic mutation from C to G, leading to an amino acid substitution from Ser to Cys at codon 37. Among the cell lines, SCLC NCI-H1092 had a mutation from A to G, leading to an Asp to Gly substitution at codon 6, NSCLC HCC15 had a mutation from C to T, leading to a Ser to Phe substitution at codon 45, and NSCLC NCI-H358 had a mutation from A to G, leading to a Thr to Ala substitution at codon 75. One blastoma also had a somatic mutation from C to G, leading to a Ser to Cys substitution at codon 37. Among the 10 malignant mesotheliomas, the authors identified a homozygous deletion in the NCI-H28 cell line. Cloning of the rearranged fragment from NCI-H28 indicated that all the exons except exon 1 of the β-catenin gene are deleted and that the deletion junction is 13 kb downstream from exon 1. Furthermore, Northern blot anal. of 26 lung cancer and eight mesothelioma cell line RNAs detected ubiquitous expression of the β-catenin messages except NCI-H28, although Western blot anal. showed that relatively less amts. of protein products were expressed in some of lung cancer cell lines. The authors' findings suggest that the β-catenin gene is infrequently mutated in lung cancer and that the NCI-H28 homozygous deletion of the β-catenin gene might indicate the possibility of a new tumor suppressor gene residing in this region at 3p21.3, where various types of human cancers show frequent allelic loss.
    29. 29
      Li, K.; Pan, W.-T.; Ma, Y.-B.; Xu, X.-L.; Gao, Y.; He, Y.-Q.; Wei, L.; Zhang, J.-W. BMX activates Wnt/β-catenin signaling pathway to promote cell proliferation and migration in breast cancer. Breast Cancer 2020, 27 (3), 363– 371,  DOI: 10.1007/s12282-019-01024-8
      29
      BMX activates Wnt/β-catenin signaling pathway to promote cell proliferation and migration in breast cancer
      Li Kai; Pan Wen-Ting; Ma Yan-Bin; Xu Xiao-Long; Gao Yang; He Yan-Qi; Wei Lei; Zhang Jing-Wei
      Breast cancer (Tokyo, Japan) (2020), 27 (3), 363-371 ISSN:.
      BACKGROUND: Breast cancer has become a dangerous killer for the female, which seriously threatened women's life, leading to huge pressures to society. The present study assessed the mechanism underlying the involvement of bone marrow tyrosine kinase on chromosome X (BMX) in breast cancer development. METHODS: The expression of BMX was examined by qPCR and immunohistochemistry. The effect of BMX on cell proliferation and migration was detected by Clone formation assay and Transwell assay. In vitro study, the correlation of BMX with Wnt/β-catenin pathway was explored by western blot and TOP/FOP flash assay. RESULTS: In the present study, we found that BMX was up-regulated in breast cancer, which was associated with the tumor differentiation and TNM stage. Oncogenic BMX enhanced the ability of breast cancer cell proliferation and migration. Furthermore, BMX could up-regulate the protein expression levels of p-β-catenin (Y142), p-β-catenin(Y654) and inhibit the expression level of p-β-catenin (S33/37), thus activating Wnt/β-catenin pathway in MCF-7 and MDA-MB-231 cells. In addition, we revealed that BMX promoted GSK3β phosphorylation, which suppressed the degradation of β-catenin. CONCLUSIONS: In this study, we identified that BMX-activated Wnt/β-catenin signaling pathway, playing an oncogenic role in breast cancer, suggesting that BMX could become a potential treatment target of breast cancer.
    30. 30
      Zyla, R. E.; Olkhov-Mitsel, E.; Amemiya, Y.; Bassiouny, D.; Seth, A.; Djordjevic, B.; Nofech-Mozes, S.; Parra-Herran, C. CTNNB1Mutations and Aberrant β-Catenin Expression in Ovarian Endometrioid Carcinoma: Correlation With Patient Outcome. American journal of surgical pathology 2021, 45 (1), 68– 76,  DOI: 10.1097/PAS.0000000000001553
      30
      CTNNB1 Mutations and Aberrant β-Catenin Expression in Ovarian Endometrioid Carcinoma: Correlation With Patient Outcome
      Zyla Roman E; Seth Arun; Djordjevic Bojana; Nofech-Mozes Sharon; Parra-Herran Carlos; Zyla Roman E; Olkhov-Mitsel Ekaterina; Bassiouny Dina; Seth Arun; Djordjevic Bojana; Nofech-Mozes Sharon; Parra-Herran Carlos; Amemiya Yutaka; Seth Arun; Bassiouny Dina
      The American journal of surgical pathology (2021), 45 (1), 68-76 ISSN:.
      CTNNB1 mutations and aberrant β-catenin expression have adverse prognosis in endometrial endometrioid carcinoma, and recent evidence suggests a prognostic role of β-catenin in ovarian endometrioid carcinoma. Thus, we aimed to determine the prognostic value of the CTNNB1 mutational status, and its correlation with β-catenin expression, in a well-annotated cohort of 51 ovarian endometrioid carcinomas. We performed immunohistochemistry for β-catenin and developed an 11-gene next-generation sequencing panel that included whole exome sequencing of CTNNB1 and TP53. Results were correlated with clinicopathologic variables including disease-free and disease-specific survival. Tumor recurrence was documented in 14 patients (27%), and cancer-related death in 8 patients (16%). CTNNB1 mutations were found in 22 cases (43%), and nuclear β-catenin in 26 cases (51%). CTNNB1 mutation highly correlated with nuclear β-catenin (P<0.05). Mutated CTNNB1 status was statistically associated with better disease-free survival (P=0.04, log-rank test) and approached significance for better disease-specific survival (P=0.07). It also correlated with earlier International Federation of Gynecology and Obstetrics stage (P<0.05). Nuclear β-catenin, TP53 mutations, age, ProMisE group, surface involvement, tumor grade and stage also correlated with disease-free survival. There was no association between membranous β-catenin expression and disease-free or disease-specific survival. CTNNB1 mutations and nuclear β-catenin expression are associated with better progression-free survival in patients with OEC. This relationship may be in part due to a trend of CTNNB1-mutated tumors to present at early stage. β-catenin immunohistochemistry may serve as a prognostic biomarker and a surrogate for CTNN1B mutations in the evaluation of patients with ovarian endometrioid neoplasia, particularly those in reproductive-age or found incidentally without upfront staging surgery.
    31. 31
      Ferri, M.; Liscio, P.; Carotti, A.; Asciutti, S.; Sardella, R.; Macchiarulo, A.; Camaioni, E. Targeting Wnt-driven Cancers: Discovery of Novel Tankyrase Inhibitors. Eur. J. Med. Chem. 2017, 142, 506– 522,  DOI: 10.1016/j.ejmech.2017.09.030
      31
      Targeting Wnt-driven cancers: Discovery of novel tankyrase inhibitors
      Ferri, Martina; Liscio, Paride; Carotti, Andrea; Asciutti, Stefania; Sardella, Roccaldo; Macchiarulo, Antonio; Camaioni, Emidio
      European Journal of Medicinal Chemistry (2017), 142 (), 506-522CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
      A review. Recent years have seen substantially heightened interest in the discovery of tankyrase inhibitors (TNKSi) as new promising anticancer agents. In this framework, the aim of this review article is focused on the description of potent TNKSi also endowed with disruptor activity toward the Wnt/β-catenin signaling pathway. Beginning with an overview of the most characterized TNKSi deriving from several drug design approaches and classifying them on the basis of the mol. interactions with the target, the authors discuss only those ones acting against Wnt cancer cell lines. In addn., comprehensive structure property relationships (SPR) emerging from the hit evolution processes and preclin. results are provided. The authors then review the most promising TNKSi hitherto reported in literature, acting in vivo models of Wnt-driven cancers. Some out-looks on current issues and future directions in this field are also discussed.
    32. 32
      Buchstaller, H. P.; Anlauf, U.; Dorsch, D.; Kögler, S.; Kuhn, D.; Lehmann, M.; Leuthner, B.; Lodholz, S.; Musil, D.; Radtki, D.; Rettig, C.; Ritzert, C.; Rohdich, F.; Schneider, R.; Wegener, A.; Weigt, S.; Wilkinson, K.; Esdar, C. Optimization of a Screening Hit toward M2912, an Oral Tankyrase Inhibitor with Antitumor Activity in Colorectal Cancer Models. J. Med. Chem. 2021, 64 (14), 10371– 10392,  DOI: 10.1021/acs.jmedchem.1c00800
      32
      Optimization of a Screening Hit toward M2912, an Oral Tankyrase Inhibitor with Antitumor Activity in Colorectal Cancer Models
      Buchstaller, Hans-Peter; Anlauf, Uwe; Dorsch, Dieter; Koegler, Sarah; Kuhn, Daniel; Lehmann, Martin; Leuthner, Birgitta; Lodholz, Sara; Musil, Djordje; Radtki, Daniela; Rettig, Corinna; Ritzert, Claudio; Rohdich, Felix; Schneider, Richard; Wegener, Ansgar; Weigt, Stefan; Wilkinson, Kai; Esdar, Christina
      Journal of Medicinal Chemistry (2021), 64 (14), 10371-10392CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      The identification of a screening hit series and its optimization through scaffold hopping and SAR exploration was described. The systematic assessment delivered M2912 I a compd. with an optimal balance between excellent TNKS potency, exquisite PARP selectivity, and a predicted human PK compatible with once daily oral dosing. Modulation of cellular Wnt pathway activity and significant tumor growth inhibition was demonstrated with this compd. in colorectal xenograft models in vivo.
    33. 33
      Buchstaller, H. P.; Anlauf, U.; Dorsch, D.; Kuhn, D.; Lehmann, M.; Leuthner, B.; Musil, D.; Radtki, D.; Ritzert, C.; Rohdich, F.; Schneider, R.; Esdar, C. Discovery and Optimization of 2-Arylquinazolin-4-ones into a Potent and Selective Tankyrase Inhibitor Modulating Wnt Pathway Activity. J. Med. Chem. 2019, 62 (17), 7897– 7909,  DOI: 10.1021/acs.jmedchem.9b00656
      33
      Discovery and Optimization of 2-Arylquinazolin-4-ones into a Potent and Selective Tankyrase Inhibitor Modulating Wnt Pathway Activity
      Buchstaller, Hans-Peter; Anlauf, Uwe; Dorsch, Dieter; Kuhn, Daniel; Lehmann, Martin; Leuthner, Birgitta; Musil, Djordje; Radtki, Daniela; Ritzert, Claudio; Rohdich, Felix; Schneider, Richard; Esdar, Christina
      Journal of Medicinal Chemistry (2019), 62 (17), 7897-7909CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Tankyrases 1 and 2 (TNKS1/2) are promising pharmacol. targets which recently gained interest for anticancer therapy in Wnt pathway dependent tumors. 2-Aryl-quinazolinones were identified and optimized into potent tankyrase inhibitors through SAR exploration around the quinazolinone core and the 4'-position of the Ph residue. These efforts were supported by anal. of TNKS X-ray and Watermap structures and resulted in compd. 5k(I), a potent, selective tankyrase inhibitor with favorable pharmacokinetic properties. The X-ray structure of I in complex with TNKS1 was solved and confirmed the design hypothesis. Modulation of Wnt pathway activity was demonstrated with this compd. in a colorectal xenograft model in vivo.
    34. 34
      Mehta, C. C.; Bhatt, H. G. Tankyrase inhibitors as Antitumor Agents: a Patent Update (2013–2020). Expert Opinion on Therapeutic Patents 2021, 31 (7), 645– 661,  DOI: 10.1080/13543776.2021.1888929
      34
      Tankyrase inhibitors as antitumor agents: a patent update (2013 - 2020)
      Mehta, Chirag C.; Bhatt, Hardik G.
      Expert Opinion on Therapeutic Patents (2021), 31 (7), 645-661CODEN: EOTPEG; ISSN:1354-3776. (Taylor & Francis Ltd.)
      IntroductionTankyrase inhibitors gained significant attention as therapeutic targets in oncol. because of their potency. Their primary role in inhibiting the Wnt signaling pathway makes them an important class of compds. with the potential to be used as a combination therapy in future treatments of colorectal cancer. Areas coveredThis review describes pertinent work in the development of tankyrase inhibitors with a great emphasis on the recently patented TNKS inhibitors published from 2013 to 2020. This article also highlights a couple of promising candidates having tankyrase inhibitory effects and are currently undergoing clin. trials. Expert opinionFollowing the successful clin. applications of PARP inhibitors, tankyrase inhibition has gained significant attention in the research community as a target with high therapeutic potential. The ubiquitous role of tankyrase in cellular homeostasis and Wnt-dependent tumor proliferation brought difficulties for researchers to strike the right balance between potency and on-target toxicity. The need for novel tankyrase inhibitors with a better ADMET profile can introduce an addnl. regimen in treating various malignancies in monotherapy or adjuvant therapy. The development of combination therapies, including tankyrase inhibitors with or without PARP inhibitory properties, can potentially benefit the larger population of patients with unmet medical needs.
    35. 35
      Karlberg, T.; Markova, N.; Johansson, I.; Hammarström, M.; Schütz, P.; Weigelt, J.; Schüler, H. Structural Basis for the Interaction between Tankyrase-2 and a Potent Wnt-Signaling Inhibitor. J. Med. Chem. 2010, 53 (14), 5352– 5355,  DOI: 10.1021/jm100249w
      35
      Structural Basis for the Interaction between Tankyrase-2 and a Potent Wnt-Signaling Inhibitor
      Karlberg, Tobias; Markova, Natalia; Johansson, Ida; Hammarstrom, Martin; Schutz, Patrick; Weigelt, Johan; Schuler, Herwig
      Journal of Medicinal Chemistry (2010), 53 (14), 5352-5355CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      We report two crystal structures of the PARP domain of human tankyrase-2 (TNKS2). Tankyrases are involved in fundamental cellular processes such as telomere homeostasis and Wnt signaling. The complex of TNKS2 with the potent inhibitor XAV939 provides insights into the mol. basis of the strong interaction and suggests routes for further development of tankyrase inhibitors.
    36. 36
      Narwal, M.; Haikarainen, T.; Fallarero, A.; Vuorela, P. M.; Lehtiö, L. Screening and Structural Analysis of Flavones Inhibiting Tankyrases. J. Med. Chem. 2013, 56 (9), 3507– 3517,  DOI: 10.1021/jm3018783
      36
      Screening and Structural Analysis of Flavones Inhibiting Tankyrases
      Narwal, Mohit; Haikarainen, Teemu; Fallarero, Adyary; Vuorela, Pia M.; Lehtio, Lari
      Journal of Medicinal Chemistry (2013), 56 (9), 3507-3517CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Flavonoids are known for their beneficial effects on human health, and therefore the therapeutic potential of these compds. have been extensively studied. Flavone has been previously identified as a tankyrase inhibitor, and to further elucidate whether tankyrases would be inhibited by other flavonoids, the authors performed a systematic screening of tankyrase 2 inhibitory activity using 500 natural and naturally derived flavonoids covering nine different flavonoid classes. All identified tankyrase inhibitors were flavones. The authors report crystal structures of all the hit compds. in complex with the catalytic domain of human tankyrase 2. Flavone derivs. in all 10 crystal structures bind to the nicotinamide binding site of tankyrase 2. Potencies of the active flavones toward tankyrases vary between 50 nM and 1.1 μM, and flavones show up to 200-fold selectivity for tankyrases over ARTD1. The mol. details of the interactions revealed by cocrystal structures efficiently describe the properties of potent flavone derivs. inhibiting tankyrases.
    37. 37
      Narwal, M.; Koivunen, J.; Haikarainen, T.; Obaji, E.; Legala, O. E.; Venkannagari, H.; Joensuu, P.; Pihlajaniemi, T.; Lehtiö, L. Discovery of Tankyrase Inhibiting Flavones with Increased Potency and Isoenzyme Selectivity. J. Med. Chem. 2013, 56 (20), 7880– 7889,  DOI: 10.1021/jm401463y
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      Discovery of Tankyrase Inhibiting Flavones with Increased Potency and Isoenzyme Selectivity
      Narwal, Mohit; Koivunen, Jarkko; Haikarainen, Teemu; Obaji, Ezeogo; Legala, Ongey E.; Venkannagari, Harikanth; Joensuu, Paivi; Pihlajaniemi, Taina; Lehtio, Lari
      Journal of Medicinal Chemistry (2013), 56 (20), 7880-7889CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Tankyrases are ADP-ribosyltransferases that play key roles in various cellular pathways, including the regulation of cell proliferation, and thus, they are promising drug targets for the treatment of cancer. Flavones have been shown to inhibit tankyrases and we report here the discovery of more potent and selective flavone derivs. Com. available flavones with single substitutions were used for structure-activity relation studies, and cocrystal structures of the 18 hit compds. were analyzed to explain their potency and selectivity. The most potent inhibitors were also tested in a cell-based assay, which demonstrated that they effectively antagonize Wnt signaling. To assess selectivity, they were further tested against a panel of homologous human ADP-ribosyltransferases. The most effective compd.(I; MN-64), showed 6 nM potency against tankyrase 1, isoenzyme selectivity, and Wnt signaling inhibition. This work forms a basis for rational development of flavones as tankyrase inhibitors and guides the development of other structurally related inhibitors.
    38. 38
      Sorkun, M. C.; Mullaj, D.; Koelman, J. M. V. A.; Er, S. ChemPlot, A Python Library for Chemical Space Visualization. Chemistry-Europe 2022, 2 (7), e202200005  DOI: 10.1002/cmtd.202200005
      There is no corresponding record for this reference.