Selective inhibitors and tailored activity probes for lipoprotein-associated phospholipase A2

被引：26

作者：

Nagano, Joseph M. G. ^{[1
,2
]}

Hsu, Ku-Lung ^{[1
,2
]}

Whitby, Landon R. ^{[1
,2
]}

Niphakis, Micah J. ^{[1
,2
]}

Speers, Anna E. ^{[1
,2
]}

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

Spicer, Timothy ^{[4
]}

Fernandez-Vega, Virneliz ^{[4
]}

Ferguson, Jill ^{[1
,3
]}

Hodder, Peter ^{[4
,5
]}

Srinivasan, Prabhavathi ^{[6
]}

Gonzalez, Tara D. ^{[6
]}

Rosen, Hugh ^{[1
,3
]}

Bahnson, Brian J. ^{[6
]}

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, 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

[6] Univ Delaware, Dept Chem & Biochem, Newark, DE 19716 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 03期

基金：

美国国家卫生研究院;

关键词：

Phospholipase; Inhibitor; Screening; Proteomics; ACTIVATING-FACTOR ACETYLHYDROLASE; CORONARY-ARTERY-DISEASE; PROSTATE-CANCER; HEART-DISEASE; IDENTIFICATION; METABOLISM; DARAPLADIB; MECHANISM; ENZYMES; PLA2G7;

D O I：

10.1016/j.bmcl.2012.11.061

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2) or PLA(2)G7) binds to low-density lipoprotein (LDL) particles, where it is thought to hydrolyze oxidatively truncated phospholipids. Lp-PLA(2) has also been implicated as a pro-tumorigenic enzyme in human prostate cancer. Several inhibitors of Lp-PLA(2) have been described, including darapladib, which is currently in phase 3 clinical development for the treatment of atherosclerosis. The selectivity that darapladib and other Lp-PLA(2) inhibitors display across the larger serine hydrolase family has not, however, been reported. Here, we describe the use of both general and tailored activity-based probes for profiling Lp-PLA(2) and inhibitors of this enzyme in native biological systems. We show that both darapladib and a novel class of structurally distinct carbamate inhibitors inactivate Lp-PLA(2) in mouse tissues and human cell lines with high selectivity. Our findings thus identify both inhibitors and chemoproteomic probes that are suitable for investigating Lp-PLA(2) function in biological systems. (c) 2012 Elsevier Ltd. All rights reserved.

引用

页码：839 / 843

页数：5

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