ACS medicinal chemistry letters · 2023
Optimization of 1,2,4-Triazole-Based p97 Inhibitors for the Treatment of Cancer.
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LaPorte Matthew G, Alverez Celeste, Chatterley Alexander, Kovaliov Marina, Carder Evan J, Houghton Michael J, Lim Chaemin, Miller Eric R, Samankumara Lalith P, Liang Mary, Kerrigan Kaylan, Yue Zhizhou, Li Shan, Tomaino Francesca, Wang Feng, Green Neal, Stott Gordon M, Srivastava Apurva, Chou Tsui-Fen, Wipf Peter, Huryn Donna M
Аннотация
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.