Selective Inhibitor of Platelet-Activating Factor Acetylhydrolases 1b2 and 1b3 That Impairs Cancer Cell Survival

被引：40

作者：

Chang, Jae Won ^{[1
,2
]}

Zuhl, Andrea M. ^{[1
,2
]}

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

Niessen, Sherry ^{[1
,2
]}

Brown, Steven J. ^{[3
]}

Mulvihill, Melinda M. ^{[6
]}

Fan, Yi Chiao ^{[7
]}

Spicer, Timothy P. ^{[4
]}

Southern, Mark ^{[4
]}

Scampavia, Louis ^{[4
]}

Fernandez-Vega, Virneliz ^{[4
]}

Dix, Melissa M. ^{[1
,2
]}

Cameron, Michael D. ^{[5
]}

Hodder, Peter S. ^{[4
]}

Rosen, Hugh ^{[3
]}

Nomura, Daniel. K. ^{[6
]}

Kwon, Ohyun ^{[7
]}

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

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

机构：

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

[2] Scripps Res Inst, Dept Physiol Chem, 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 Calif Berkeley, Dept Nutr Sci & Toxicol, Berkeley, CA 94720 USA

[7] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA

来源：

ACS CHEMICAL BIOLOGY | 2015年 / 10卷 / 04期

基金：

美国国家科学基金会; 美国国家卫生研究院;

关键词：

TARGET ENGAGEMENT; IN-VIVO; PROTEIN; SUBUNIT; COMPLEX; IDENTIFICATION; PROTEOMICS; DISCOVERY; LIBRARY; SCREEN;

D O I：

10.1021/cb500893q

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Platelet-activating factor acetylhydrolases (PAFAHs) 1b2 and 1b3 are poorly characterized serine hydrolases that form a complex with a noncatalytic protein (1b1) to regulate brain development, spermatogenesis, and cancer pathogenesis. Determining physiological substrates and biochemical functions for the PAFAH1b complex would benefit from selective chemical probes that can perturb its activity in living systems. Here, we report a class of tetrahydropyridine reversible inhibitors of PAFAH1b2/3 discovered using a fluorescence polarization-activity-based protein profiling (fluopol-ABPP) screen of the NIH 300 000+ compound library. The most potent of these agents, P11, exhibited IC50 values of similar to 40 and 900 nM for PAFAH1b2 and 1b3, respectively. We confirm selective inhibition of PAFAH1b2/3 in cancer cells by P11 using an ABPP protocol adapted for in situ analysis of reversible inhibitors and show that this compound impairs tumor cell survival, supporting a role for PAFAH1b2/3 in cancer.

引用

页码：925 / 932

页数：8

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