2. Academic Validation
  3. Antitumor Efficacy of 1,2,4-Triazole-Based VCP/p97 Allosteric Inhibitors

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

  • J Med Chem. 2025 Jul 24;68(14):14465-14494. doi: 10.1021/acs.jmedchem.5c00507.
Neal Green 1,  Matthew G LaPorte 2,  William Paquette 3,  Sipak Joyasawal 2,  Pravat Mondal 2,  Zoe Vaughn 2,  Evan J Carder 2,  Mary Liang 2,  Li Shan 4,  Feng Wang 4,  Francesca Tomaino 1,  Apurva Srivastava 1,  Andrew Flint 1,  William J Moore 1,  Tsui-Fen Chou 4,  Gordon M Stott 1,  Mark Wolf 5,  Peter Wipf 2,  Donna M Huryn 2
Affiliations

Affiliations

  • 1 NExT Program Support, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, Maryland 21702, United States.
  • 2 University of Pittsburgh Chemical Diversity Center, Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.
  • 3 Department of Medicinal Chemistry, Curia Global Inc, 33 Riverside Ave, Rensselaer, New York 12144, United States.
  • 4 Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, United States.
  • 5 Department of Medicinal Chemistry, The Conventus, Curia Global Inc, 1001 Main St, Buffalo, New York 14203, United States.
PMID: 40605370 DOI: 10.1021/acs.jmedchem.5c00507
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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