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

Matthew G LaPorte; Celeste Alverez; Alexander Chatterley; Marina Kovaliov; Evan J Carder; Michael J Houghton; Chaemin Lim; Eric R Miller; Lalith P Samankumara; Mary Liang; Kaylan Kerrigan; Zhizhou Yue; Shan Li; Francesca Tomaino; Feng Wang; Neal Green; Gordon M Stott; Apurva Srivastava; Tsui-Fen Chou; Peter Wipf; Donna M Huryn

doi:10.1021/acsmedchemlett.3c00163

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. eCollection 2023 Jul 13.

Authors

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 Li⁴, Francesca Tomaino⁵, Feng Wang⁴, Neal Green⁵, Gordon M Stott⁵, Apurva Srivastava⁵, Tsui-Fen Chou⁴, 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.

Abstract

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