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Antitumor Efficacy of 1,2,4-Triazole-Based VCP/p97 Allosteric Inhibitors

  1. Author:
    Green, Neal [ORCID]
    LaPorte, Matthew G
    Paquette, William
    Joyasawal, Sipak
    Mondal, Pravat
    Vaughn, Zoe
    Carder, Evan J
    Liang, Mary
    Shan, Li
    Wang, Feng
    Tomaino, Francesca [ORCID]
    Srivastava,Apurva
    Flint,Andrew
    Moore,William
    Chou, Tsui-Fen [ORCID]
    Stott,Gordon
    Wolf, Mark
    Wipf, Peter [ORCID]
    Huryn, Donna M [ORCID]

  2. Author Address

    NExT Program Support, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, Maryland 21702, United States., University of Pittsburgh Chemical Diversity Center, Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States., Department of Medicinal Chemistry, Curia Global Inc, 33 Riverside Ave, Rensselaer, New York 12144, United States., Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, United States., Department of Medicinal Chemistry, The Conventus, Curia Global Inc, 1001 Main St, Buffalo, New York 14203, United States.,
    1. Year: 2025
    2. Date: Jul 02
    3. Epub Date: 2025 07 02
  2. Journal: Journal of Medicinal Chemistry
  4. Type of Article: Article
  1. Abstract:

    The AAA ATPase p97 (VCP) plays a crucial role in maintaining protein homeostasis through the ubiquitin-proteosome pathway, as well as other mechanisms. Due to the increased mutational load and protein quality control failures in cancer cells, p97 is a potential target for cancer therapy. Here, we highlight the optimization of the previously reported 3-thioalkyl-1,2,4-triazol-pyridyl allosteric inhibitor scaffold and identify two compounds (25 and 38) with low-nanomolar biochemical potency, submicromolar cellular inhibition, in vivo effects on biomarkers of VCP inhibition, and antitumor efficacy in mouse xenograft tumor models. Furthermore, compound 38 demonstrated robust inhibition of VCP ATP-site mutant proteins and growth of cells resistant to the known ATP-competitive inhibitor CB-5083.

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External Sources

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  2. DOI: 10.1021/acs.jmedchem.5c00507
  3. PMID: 40605370

Library Notes

  1. Fiscal Year: FY2024-2025
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