1. Optimization of 1,2,4-Triazole-Based p97 Inhibitors for the Treatment of Cancer.
- Author
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LaPorte MG, Alverez C, Chatterley A, Kovaliov M, Carder EJ, Houghton MJ, Lim C, Miller ER, Samankumara LP, Liang M, Kerrigan K, Yue Z, Li S, Tomaino F, Wang F, Green N, Stott GM, Srivastava A, Chou TF, Wipf P, and Huryn DM
- 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., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)
- Published
- 2023
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