2. Academic Validation
  3. Optimization of 1,2,4-Triazole-Based p97 Inhibitors for the Treatment of Cancer

Optimization of 1,2,4-Triazole-Based p97 Inhibitors for the Treatment of Cancer

  • ACS Med Chem Lett. 2023 Jun 21;14(7):977-985. doi: 10.1021/acsmedchemlett.3c00163.
Matthew G LaPorte 1 2,  Celeste Alverez 1 3,  Alexander Chatterley 1 2,  Marina Kovaliov 1 2,  Evan J Carder 1 2,  Michael J Houghton 1 2,  Chaemin Lim 1 2,  Eric R Miller 1 2,  Lalith P Samankumara 1 2,  Mary Liang 1 3,  Kaylan Kerrigan 1 2,  Zhizhou Yue 1 2,  Shan Li 4,  Francesca Tomaino 5,  Feng Wang 4,  Neal Green 5,  Gordon M Stott 5,  Apurva Srivastava 5,  Tsui-Fen Chou 4,  Peter Wipf 1 2 3,  Donna M Huryn 1 3
Affiliations

Affiliations

  • 1 University of Pittsburgh Chemical Diversity Center, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.
  • 2 Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.
  • 3 Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.
  • 4 Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, United States.
  • 5 Leidos Biomedical Research, Inc., Frederick, Maryland 21702, United States.
PMID: 37465292 DOI: 10.1021/acsmedchemlett.3c00163
Abstract

The AAA+ ATPase p97 (valosin-containing protein, VCP) is a master regulator of protein homeostasis and therefore represents a novel target for Cancer therapy. Starting from a known allosteric inhibitor, NMS-873, we systematically optimized this scaffold, in particular, by applying a benzene-to-acetylene isosteric replacement strategy, specific incorporation of F, and eutomer/distomer identification, which led to compounds that exhibited nanomolar biochemical and cell-based potency. In cellular pharmacodynamic assays, robust effects on biomarkers of p97 inhibition and Apoptosis, including increased levels of ubiquitinated proteins, CHOP and cleaved Caspase 3, were observed. Compound (R)-29 (UPCDC-30766) represents the most potent allosteric inhibitor of p97 reported to date.

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