Bioorganic & medicinal chemistry letters · 2012
Selective inhibitors and tailored activity probes for lipoprotein-associated phospholipase A(2).
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Nagano Joseph M G, Hsu Ku-Lung, Whitby Landon R, Niphakis Micah J, Speers Anna E, Brown Steven J, Spicer Timothy, Fernandez-Vega Virneliz, Ferguson Jill, Hodder Peter, Srinivasan Prabhavathi, Gonzalez Tara D, Rosen Hugh, Bahnson Brian J, Cravatt Benjamin F
Аннотация
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.