Selective proteolysis represents a cutting-edge therapeutic approach that is garnering global interest due to its capacity to eradicate pathogenic biomolecules within cellular environments. For instance, the PROTAC technology brings the ubiquitin proteasome system degradation machinery in close proximity of the KRAS^G12D mutant protein for initiating its degradation and the clearing of abnormal protein debris with unparallel precision, which provides an edge over traditional protein inhibition. This Patent Highlight provides exemplary PROTAC compounds having activity as inhibitors or degraders of the G12D mutant KRAS protein.

Toll-like receptors and interleukin-1 receptor directly interact with intracellular interleukin receptor associated kinase (IRAK) family members to initiate innate immune and inflammatory responses following activation by pathogens. The IRAK family members are involved in linking the innate immune response to the pathogenesis of various diseases, including cancers, non-infectious immune disorders, and metabolic disorders. The Patent Highlight showcases exemplary PROTAC compounds that exhibit a broad range of pharmacological activities associated with degradation of protein targets for the treatment of cancer.

The anti-apoptotic BCL-2 protein family members, including BCL-2, BCL-XL, and MCL-1, have been established as promising therapeutic targets for cancer treatment, as evidenced by the FDA approval of venetoclax in 2016. Researchers have redoubled their efforts to design analogs that exhibit enhanced pharmacokinetic and pharmacodynamic characteristics. This Patent Highlight features PROTAC compounds that demonstrate potent and selective BCL-2 degradation, with potential applications in the treatment of cancer, autoimmune disorders, and immune system diseases.

Described herein are aryl hydrocarbon receptor agonists, their pharmaceutical compositions, the use of such compounds in treating immune-mediated diseases, in particular psoriasis, and processes for preparing such compounds.

Provided herein are monoacylglycerol lipase modulators, pharmaceutical compositions, use of such compounds in treating autism spectrum disorders and processes for preparing such compounds.

Provided herein are 1,2,4-triazine derivatives used as NLRP3 inhibitors, their pharmaceutical compositions, the use of such compounds in treating diseases and processes for preparing such compounds.

Provided herein are novel thienopyrrole compounds, pharmaceutical compositions, use of such compounds in treating autoimmune diseases and inflammatory conditions, and processes for preparing such compounds.

Described herein are novel serine-arginine protein kinase (SRPK) inhibitors, their pharmaceutical compositions, the use of such compounds in treating cancer, and processes for preparing such compounds.

Provided herein are novel imidazotriazine derivatives used as IL-17 modulators, their pharmaceutical compositions, the use of such compounds in treating inflammatory and autoimmune disorders, and processes for preparing such compounds.

Provided herein are novel tricyclic compounds as KRAS inhibitors, pharmaceutical compositions, use of such compounds in treating cancer and processes for preparing such compounds.

Life is constructed primarily using a toolbox of 20 canonical amino acids─relying upon these building blocks for the assembly of proteins and peptides that regulate nearly every cellular task, including cell structure, function, and maintenance. While Nature continues to be a source of inspiration for drug discovery, medicinal chemists are not beholden to only 20 canonical amino acids and have begun to explore non-canonical amino acids (ncAAs) for the construction of designer peptides with improved drug-like properties. However, as our toolbox of ncAAs expands, drug hunters are encountering new challenges in approaching the iterative peptide design–make–test–analyze cycle with a seemingly boundless set of building blocks. This Microperspective focuses on new technologies that are accelerating ncAA interrogation in peptide drug discovery (including HELM notation, late-stage functionalization, and biocatalysis) while shedding light on areas where further investment could not only accelerate the discovery of new medicines but also improve downstream development.

Wee1 is a tyrosine kinase that is highly expressed in several cancer types. Wee1 inhibition can lead to suppression of tumor cell proliferation and sensitization of cells to the effects of DNA-damaging agents. AZD1775 is a nonselective Wee1 inhibitor for which myelosuppression has been observed as a dose-limiting toxicity. We have applied structure-based drug design (SBDD) to rapidly generate highly selective Wee1 inhibitors that demonstrate better selectivity than AZD1775 against PLK1, which is known to cause myelosuppression (including thrombocytopenia) when inhibited. While selective Wee1 inhibitors described herein still achieved in vitro antitumor efficacy, thrombocytopenia was still observed in vitro.

Increasing the variety of antimicrobial peptides is crucial in meeting the global challenge of multi-drug-resistant bacterial pathogens. While several deep-learning-based peptide design pipelines are reported, they may not be optimal in data efficiency. High efficiency requires a well-compressed latent space, where optimization is likely to fail due to numerous local minima. We present a multi-objective peptide design pipeline based on a discrete latent space and D-Wave quantum annealer with the aim of solving the local minima problem. To achieve multi-objective optimization, multiple peptide properties are encoded into a score using non-dominated sorting. Our pipeline is applied to design therapeutic peptides that are antimicrobial and non-hemolytic at the same time. From 200 000 peptides designed by our pipeline, four peptides proceeded to wet-lab validation. Three of them showed high anti-microbial activity, and two are non-hemolytic. Our results demonstrate how quantum-based optimizers can be taken advantage of in real-world medical studies.

The recent success of fragment-based drug discovery (FBDD) is inextricably linked to adequate library design. To guide the design of our fragment libraries, we have constructed an automated workflow in the open-source KNIME software. The workflow considers chemical diversity and novelty of the fragments, and can also take into account the three-dimensional (3D) character. This design tool can be used to create large and diverse libraries but also to select a small number of representative compounds as a focused set of unique screening compounds to enrich existing fragment libraries. To illustrate the procedures, the design and synthesis of a 10-membered focused library is reported based on the cyclopropane scaffold, which is underrepresented in our existing fragment screening library. Analysis of the focused compound set indicates significant shape diversity and a favorable overall physicochemical profile. By virtue of its modular setup, the workflow can be readily adjusted to design libraries that focus on properties other than 3D shape.

Drug resistance mutations emerging during the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) inhibitors represent a major challenge in personalized cancer treatment and require constant development of new inhibitors. For the covalent irreversible EGFR inhibitor osimertinib, the predominant resistance mechanism is the acquired C797S mutation, which abolishes the covalent anchor point and thus results in a dramatic loss in potency. In this study, we present next-generation reversible EGFR inhibitors with the potential to overcome this EGFR-C797S resistance mutation. For this, we combined the reversible methylindole-aminopyrimidine scaffold known from osimertinib with the affinity driving isopropyl ester of mobocertinib. By occupying the hydrophobic back pocket, we were able to generate reversible inhibitors with subnanomolar activity against EGFR-L858R/C797S and EGFR-L858R/T790M/C797S with cellular activity on EGFR-L858R/C797S dependent Ba/F3 cells. Additionally, we were able to resolve cocrystal structures of these reversible aminopyrimidines, which will guide further inhibitor design toward C797S-mutated EGFR.

Current therapy against melanoma relies on surgical treatment or, in alternative, on conventional drug therapy. Often these therapeutic agents are ineffective due to the development of resistance phenomena. For this purpose, chemical hybridization emerged as an effective strategy to overcome the development of drug resistance. In this study, a series of molecular hybrids were synthesized combining the sesquiterpene artesunic acid with a panel of phytochemical coumarins. Cytotoxicity, antimelanoma effect, and cancer selectivity of the novel compounds were evaluated by MTT assay on primary and metastatic cells and on healthy fibroblasts as a reference. The two most active compounds showed lower cytotoxicity and higher activity against metastatic melanoma than paclitaxel and artesunic acid. Further tests, including cellular proliferation, apoptosis, confocal microscopy, and MTT analyses in the presence of an iron chelating agent, were conducted with the aim of tentatively addressing the mode of action and the pharmacokinetic profile of selected compounds.

The mitogen-activated protein kinase signaling cascade is conserved across eukaryotes, where it plays a critical role in the regulation of activities including proliferation, differentiation, and stress responses. This pathway propagates external stimuli through a series of phosphorylation events, which allows external signals to influence metabolic and transcriptional activities. Within the cascade, MEK, or MAP2K, enzymes occupy a molecular crossroads immediately upstream to significant signal divergence and cross-talk. One such kinase, MAP2K7, also known as MEK7 and MKK7, is a protein of great interest in the molecular pathophysiology underlying pediatric T cell acute lymphoblastic leukemia (T-ALL). Herein, we describe the rational design, synthesis, evaluation, and optimization of a novel class of irreversible MAP2K7 inhibitors. With a streamlined one-pot synthesis, favorable in vitro potency and selectivity, and promising cellular activity, this novel class of compounds wields promise as a powerful tool in the study of pediatric T-ALL.

The cannabinoids cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) undergo extensive oxidative metabolism in the liver. Although cytochromes P450 form the primary, pharmacologically active, hydroxylated metabolites of CBD and THC, less is known about the enzymes that generate the major in vivo circulating metabolites of CBD and THC, 7-carboxy-CBD and 11-carboxy-THC, respectively. The purpose of this study was to elucidate the enzymes involved in forming these metabolites. Cofactor dependence experiments with human liver subcellular fractions revealed that 7-carboxy-CBD and 11-carboxy-THC formation is largely dependent on cytosolic NAD⁺-dependent enzymes, with lesser contributions from NADPH-dependent microsomal enzymes. Experiments with chemical inhibitors provided evidence that 7-carboxy-CBD formation is mainly dependent on aldehyde dehydrogenases and 11-carboxy-THC formation is mediated also in part by aldehyde oxidase. This study is the first to demonstrate the involvement of cytosolic drug-metabolizing enzymes in generating major in vivo metabolites of CBD and THC and addresses a knowledge gap in cannabinoid metabolism.

Thiamine is metabolized into the coenzyme thiamine diphosphate (ThDP). Interrupting thiamine utilization leads to disease states. Oxythiamine, a thiamine analogue, is metabolized into oxythiamine diphosphate (OxThDP), which inhibits ThDP-dependent enzymes. Oxythiamine has been used to validate thiamine utilization as an anti-malarial drug target. However, high oxythiamine doses are needed in vivo because of its rapid clearance, and its potency decreases dramatically with thiamine levels. We report herein cell-permeable thiamine analogues possessing a triazole ring and a hydroxamate tail replacing the thiazolium ring and diphosphate groups of ThDP. We characterize their broad-spectrum competitive inhibition of ThDP-dependent enzymes and of Plasmodium falciparum proliferation. We demonstrate how the cellular thiamine-utilization pathway can be probed by using our compounds and oxythiamine in parallel.

Lymphocyte activation gene 3 (LAG-3) is a negative immune checkpoint that plays a key role in downregulating the immune response to cancer. Inhibition of LAG-3 interactions allows T cells to regain cytotoxic activity and reduce the immunosuppressive function of regulating T cells. We utilized a combination approach of focused screening and “SAR by catalog” to identify small molecules that function as dual inhibitors of the interactions of LAG-3 with major histocompatibility complex (MHC) class II and fibrinogen-like protein 1 (FGL1). Our top hit compound inhibited both LAG-3/MHCII and LAG-3/FGL1 interactions in biochemical binding assays with IC₅₀ values of 4.21 ± 0.84 and 6.52 ± 0.47 μM, respectively. Moreover, we have demonstrated the ability of our top hit compound to block LAG-3 interactions in cell-based assays. This work will pave the way for future drug discovery efforts aiming at the development of LAG-3-based small molecules for cancer immunotherapy.

Bivalent ligands, i.e., molecules having two ligands covalently connected by a linker, have been gathering attention since the first description of their pharmacological potential in the early 80s. However, their synthesis, particularly of labeled heterobivalent ligands, can still be cumbersome and time-consuming. We herein report a straightforward procedure for the modular synthesis of labeled heterobivalent ligands (HBLs) using dual reactive 3,6-dichloro-1,2,4,5-tetrazine as a starting material and suitable partners for sequential S_NAr and inverse electron-demand Diels–Alder (IEDDA) reactions. This assembly method conducted in a stepwise or in a sequential one-pot manner provides quick access to multiple HBLs. A conjugate combining ligands toward the prostate-specific membrane antigen (PSMA) and the gastrin-releasing peptide receptor (GRPR) was radiolabeled, and its biological activity was assessed in vitro and in vivo (receptor binding affinity, biodistribution, imaging) as an illustration that the assembly methodology preserves the tumor targeting properties of the ligands.

Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) is the first reported nonreceptor oncogenic tyrosine phosphatase connecting multiple signal transduction cascades and exerting immunoinhibitory function through the PD-1 checkpoint receptor. As part of a drug discovery program aimed at obtaining novel allosteric SHP2 inhibitors, a series of pyrazopyrazine derivatives bearing an original bicyclo[3.1.0]hexane basic moiety on the left-hand side region of the molecule were identified. We report herein the discovery process, the in vitro pharmacological profile, and the early developability features of compound 25, one of the most potent members of the series.

Poly(ADP-ribose) polymerase (PARP) plays a key role in repairing DNA damage, and several PARP inhibitors have been approved as treatments in BRCA1/2 mutated breast and ovarian cancers. Mounting evidence also supports their application as neuroprotective agents since PARP overactivation compromises the mitochondrial homeostasis by consumption of NAD⁺ reserves, leading to an increase in reactive oxygen and nitrogen species and a spike in intracellular Ca²⁺ levels. Herein, we present the synthesis and preliminary evaluation of new mitochondria-targeting PARP inhibitor prodrugs of (±)-veliparib, with the goal to advance potential neuroprotective properties without impairing the repair of damaged DNA in the nucleus.

Oxidative stress is one of the causes of progression of chronic kidney disease (CKD). Activation of the antioxidant protein regulator Nrf2 by inhibition of the Keap1–Nrf2 protein–protein interaction (PPI) is of interest as a potential treatment for CKD. We report the identification of the novel and weak PPI inhibitor 7 with good physical properties by a high throughput screening (HTS) campaign, followed by structural and computational analysis. The installation of only methyl and fluorine groups successfully provided the lead compound 25, which showed more than 400-fold stronger activity. Furthermore, these dramatic substituent effects can be explained by the analysis of using isothermal titration calorimetry (ITC). Thus, the resulting 25, which exhibited high oral absorption and durability, would be a CKD therapeutic agent because of the dose-dependent manner for up-regulation of the antioxidant protein heme oxigenase-1 (HO-1) in rat kidneys.

The development of practical synthetic protocols integrating novel technologies may enable rapid and broad exploration of chemical space in medicinal chemistry campaigns. Cross-electrophile coupling (XEC) allows the diversification of an aromatic core with alkyl halides to increase the sp³ character. Herein, we apply two alternative approaches via either photo- or electro-catalyzed XEC and showcase their complementarity to access novel tedizolid analogs. The parallel photochemical and electrochemical reactors with high light intensity and constant voltage respectively were chosen to yield good conversions, which allowed access to a wide range of derivatives in a much shorter time frame.

In recent years, photochemistry has increasingly emerged as an enabling methodology in both academia and the pharmaceutical industry. Long photolysis times and the gradual reduction of light penetration remained for many years unsolved issues for photochemical rearrangements, triggering the generation of highly reactive species in an uncontrolled fashion and causing the formation of multiple side products. The emergence of continuous-flow chemistry significantly helped to overcome these issues, thus prompting the implementation of photo-flow-based approaches for the generation of pharmaceutically relevant substructures. This Technology Note highlights the benefits of flow chemistry for photochemical rearrangements, including Wolff, Favorskii, Beckmann, Fries, and Claisen rearrangements. We showcase recent advances for photo-rearrangements in continuous flow applied to the synthesis of privileged scaffolds and active pharmaceutical ingredients.