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Low-Molecular Weight Small Molecules Can Potently Bind RNA and Affect Oncogenic Pathways in Cells

  • Blessy M. Suresh
    Blessy M. Suresh
    Department of Chemistry, The Scripps Research Institute & UF Scripps Biomedical Research, 130 Scripps Way, Jupiter, Florida 33458, United States
  • Yoshihiro Akahori
    Yoshihiro Akahori
    Department of Chemistry, The Scripps Research Institute & UF Scripps Biomedical Research, 130 Scripps Way, Jupiter, Florida 33458, United States
  • Amirhossein Taghavi
    Amirhossein Taghavi
    Department of Chemistry, The Scripps Research Institute & UF Scripps Biomedical Research, 130 Scripps Way, Jupiter, Florida 33458, United States
  • Gogce Crynen
    Gogce Crynen
    Bioinformatics and Statistics Core, The Scripps Research Institute & UF Scripps Biomedical Research, 130 Scripps Way, Jupiter, Florida 33458, United States
    More by Gogce Crynen
  • Quentin M. R. Gibaut
    Quentin M. R. Gibaut
    Department of Chemistry, The Scripps Research Institute & UF Scripps Biomedical Research, 130 Scripps Way, Jupiter, Florida 33458, United States
  • Yue Li
    Yue Li
    Department of Chemistry, The Scripps Research Institute & UF Scripps Biomedical Research, 130 Scripps Way, Jupiter, Florida 33458, United States
    More by Yue Li
  • , and 
  • Matthew D. Disney*
    Matthew D. Disney
    Department of Chemistry, The Scripps Research Institute & UF Scripps Biomedical Research, 130 Scripps Way, Jupiter, Florida 33458, United States
    *Email: [email protected]
Cite this: J. Am. Chem. Soc. 2022, 144, 45, 20815–20824
Publication Date (Web):November 2, 2022
https://doi.org/10.1021/jacs.2c08770
Copyright © 2022 American Chemical Society

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    Abstract

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    RNA is challenging to target with bioactive small molecules, particularly those of low molecular weight that bind with sufficient affinity and specificity. In this report, we developed a platform to address this challenge, affording a novel bioactive interaction. An RNA-focused small-molecule fragment collection (n = 2500) was constructed by analyzing features in all publicly reported compounds that bind RNA, the largest collection of RNA-focused fragments to date. The RNA-binding landscape for each fragment was studied by using a library-versus-library selection with an RNA library displaying a discrete structural element, probing over 12.8 million interactions, the greatest number of interactions between fragments and biomolecules probed experimentally. Mining of this dataset across the human transcriptome defined a drug-like fragment that potently and specifically targeted the microRNA-372 hairpin precursor, inhibiting its processing into the mature, functional microRNA and alleviating invasive and proliferative oncogenic phenotypes in gastric cancer cells. Importantly, this fragment has favorable properties, including an affinity for the RNA target of 300 ± 130 nM, a molecular weight of 273 Da, and quantitative estimate of drug-likeness (QED) score of 0.8. (For comparison, the mean QED of oral medicines is 0.6 ± 0.2). Thus, these studies demonstrate that a low-molecular weight, fragment-like compound can specifically and potently modulate RNA targets.

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.2c08770.

    • Supporting figures, experimental methods, synthetic methods and characterization, and computational methods (PDF).

    • List of compounds used in this study: (i) RNA-focused fragments selected from ChemDiv’s fragment library, (ii) remaining fragments not selected from ChemDiv’s fragment library, and (iii) Inforna compounds; SMILES code, UMAP parameters, rule of three (RO3) properties, and QED values (XLSX).

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    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

    This article is cited by 4 publications.

    1. Blessy M. Suresh, Yuquan Tong, Daniel Abegg, Alexander Adibekian, Jessica L. Childs-Disney, Matthew D. Disney. Altering the Cleaving Effector in Chimeric Molecules that Target RNA Enhances Cellular Selectivity. ACS Chemical Biology 2023, 18 (11) , 2385-2393. https://doi.org/10.1021/acschembio.3c00363
    2. Kangyin Pan, Ying Yao, Yiyuan Zhang, Yuang Gu, Yan Wang, Peixiang Ma, Wei Hou, Guang Yang, Shuning Zhang, Hongtao Xu. Enolate–Azide [3 + 2]-Cycloaddition Reaction Suitable for DNA-Encoded Library Synthesis. Bioconjugate Chemistry 2023, 34 (8) , 1459-1466. https://doi.org/10.1021/acs.bioconjchem.3c00235
    3. Blessy M. Suresh, Amirhossein Taghavi, Jessica L. Childs-Disney, Matthew D. Disney. Fragment-Based Approaches to Identify RNA Binders. Journal of Medicinal Chemistry 2023, 66 (10) , 6523-6541. https://doi.org/10.1021/acs.jmedchem.3c00034
    4. Jordan T. Koehn, Simon Felder, Kevin M. Weeks. Innovations in targeting RNA by fragment-based ligand discovery. Current Opinion in Structural Biology 2023, 79 , 102550. https://doi.org/10.1016/j.sbi.2023.102550

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