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.
- 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.
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.