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

• Published in: Bioorganic & medicinal chemistry letters 2013-02, Vol.23 (3), p.839-843
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: Arteriosclerosis; Enzymes; Inhibitor; Lipoproteins; Lipoproteins (low density); Phospholipase; Phospholipase A2; Phospholipids; Probes; Prostate cancer; Proteomics; Screening; serine hydrolase
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.11.061

Lipoprotein-associated phospholipase A2 (Lp-PLA2 or PLA2G7) binds to low-density lipoprotein (LDL) particles, where it is thought to hydrolyze oxidatively truncated phospholipids. Lp-PLA2 has also been implicated as a pro-tumorigenic enzyme in human prostate cancer. Several inhibitors of Lp-PLA2 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-PLA2 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-PLA2 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-PLA2 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-PLA2 function in biological systems.