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
  • 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.
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.