Year: 2023
Type: article
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.
Source: ACS Medicinal Chemistry Letters
Authors: 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
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4381510616