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

被引：3

作者：

LaPorte, Matthew G. ^{[1
,2
]}

Alverez, Celeste ^{[1
,3
]}

Chatterley, Alexander ^{[1
,2
]}

Kovaliov, Marina ^{[1
,2
]}

Carder, Evan J. ^{[1
,2
]}

Houghton, Michael J. ^{[1
,2
]}

Lim, Chaemin ^{[1
,2
]}

Miller, Eric R. ^{[1
,2
]}

Samankumara, Lalith P. ^{[1
,2
]}

Liang, Mary ^{[1
,3
]}

Kerrigan, Kaylan ^{[1
,2
]}

Yue, Zhizhou ^{[1
,2
]}

Li, Shan ^{[4
]}

Tomaino, Francesca ^{[5
]}

Wang, Feng ^{[4
]}

Green, Neal ^{[5
]}

Stott, Gordon M. ^{[5
]}

Srivastava, Apurva ^{[5
]}

Chou, Tsui-Fen ^{[4
]}

Wipf, Peter ^{[1
,2
,3
]}

Huryn, Donna M. ^{[1
,3
]}

机构：

[1] Univ Pittsburgh, Chem Divers Ctr, Pittsburgh, PA 15260 USA

[2] Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15260 USA

[3] Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA 15260 USA

[4] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA

[5] Leidos Biomed Res Inc, Frederick, MD 21702 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2023年 / 14卷 / 07期

基金：

美国国家卫生研究院;

关键词：

AAA plus ATPase; p97; allosteric inhibitor; protein homeostasis modulator; anticancer; valosin-containingprotein; NMS-873; benzene isostere; INTRINSIC CLEARANCE; INDOLE INHIBITORS; PREDICTION; VCP/P97; BINDING;

D O I：

10.1021/acsmedchemlett.3c00163

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The AAA+ ATPase p97 (valosin-containing protein, VCP)is a masterregulator of protein homeostasis and therefore represents a noveltarget 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-basedpotency. In cellular pharmacodynamic assays, robust effects on biomarkersof p97 inhibition and apoptosis, including increased levels of ubiquitinatedproteins, CHOP and cleaved caspase 3, were observed. Compound (R)-29 (UPCDC-30766) represents the most potentallosteric inhibitor of p97 reported to date.

引用

页码：977 / 985

页数：9

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