Optimization of 1,2,4-Triazole-Based p97 Inhibitors for the Treatment of Cancer
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-acety...
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| Veröffentlicht in: | ACS medicinal chemistry letters 2023-07, Vol.14 (7), p.977-985 |
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| creator | 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. |
| description | 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. |
| doi_str_mv | 10.1021/acsmedchemlett.3c00163 |
| format | Article |
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| title | Optimization of 1,2,4-Triazole-Based p97 Inhibitors for the Treatment of Cancer |
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