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Virtual screening of ultra-large chemical libraries identifies cell-permeable small-molecule inhibitors of a "non-druggable" target, STAT3 N-terminal domain

  1. Author:
    Andrade Bonilla,Pedro
    Hoop,Cody
    Stefanisko, Karen
    Tarasov,Sergey
    Sinha, Sourav
    Nicklaus,Marc
    Tarasova,Nadya

  2. Author Address

    Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, United States., Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, United States., Oncolinx Inc., New York, NY, United States., Computer-Aided Drug Design Group, Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institute of Health (NIH), Frederick, MD, United States.,
    1. Year: 2023
    2. Epub Date: 2023 04 25
  2. Journal: Frontiers in Oncology
    1. 13
    2. Pages: 1144153
  4. Type of Article: Article
  5. Article Number: 1144153
  1. Abstract:

    STAT3 N-terminal domain is a promising molecular target for cancer treatment and modulation of immune responses. However, STAT3 is localized in the cytoplasm, mitochondria, and nuclei, and thus, is inaccessible to therapeutic antibodies. Its N-terminal domain lacks deep pockets on the surface and represents a typical "non-druggable" protein. In order to successfully identify potent and selective inhibitors of the domain, we have used virtual screening of billion structure-sized virtual libraries of make-on-demand screening samples. The results suggest that the expansion of accessible chemical space by cutting-edge ultra-large virtual compound databases can lead to successful development of small molecule drugs for hard-to-target intracellular proteins. Copyright © 2023 Bonilla, Hoop, Stefanisko, Tarasov, Sinha, Nicklaus and Tarasova.

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External Sources

  1. View Full Text
  2. DOI: 10.3389/fonc.2023.1144153
  3. PMID: 37182134
  4. PMCID: PMC10167007

Library Notes

  1. Fiscal Year: FY2022-2023
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