Oxime esters as selective, covalent inhibitors of the serine hydrolase retinoblastoma-binding protein 9 (RBBP9)

被引：26

作者：

Bachovchin, Daniel A. ^{[1
,2
]}

Wolfe, Monique R. ^{[1
,2
]}

Masuda, Kim ^{[1
,2
]}

Brown, Steven J. ^{[1
,3
]}

Spicer, Timothy P. ^{[4
]}

Fernandez-Vega, Virneliz ^{[4
]}

Chase, Peter ^{[4
]}

Hodder, Peter S. ^{[4
,5
]}

Rosen, Hugh ^{[1
,3
]}

Cravatt, Benjamin F. ^{[1
,2
]}

机构：

[1] Scripps Res Inst, Dept Physiol Chem, La Jolla, CA 92037 USA

[2] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA

[3] Scripps Res Inst, Scripps Res Inst Mol Screening Ctr, La Jolla, CA 92037 USA

[4] Scripps Res Inst, Mol Screening Ctr, Lead Identificat Div, Jupiter, FL 33458 USA

[5] Scripps Res Inst, Dept Mol Therapeut, Jupiter, FL 33458 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 07期

基金：

美国国家科学基金会; 美国国家卫生研究院;

关键词：

Hydrolase; Inhibitor; Screening; Proteomics; COMPLEX PROTEOMES; ENZYME; IDENTIFICATION; CHEMISTRY; POTENT; PROBES;

D O I：

10.1016/j.bmcl.2010.02.011

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We recently described a fluorescence polarization platform for competitive activity-based protein profiling (fluopol-ABPP) that enables high-throughput inhibitor screening for enzymes with poorly characterized biochemical activity. Here, we report the discovery of a class of oxime ester inhibitors for the unannotated serine hydrolase RBBP9 from a full-deck (200,000+ compound) fluopol-ABPP screen conducted in collaboration with the Molecular Libraries Screening Center Network (MLSCN). We show that these compounds covalently inhibit RBBP9 by modifying enzyme's active site serine nucleophile and, based on competitive ABPP in cell and tissue proteomes, are selective for RBBP9 relative to other mammalian serine hydrolases. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：2254 / 2258

页数：5

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