Selective inhibitors and tailored activity probes for lipoprotein-associated phospholipase A2
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 hav...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2013-02, Vol.23 (3), p.839-843 |
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| creator | 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. |
| description | 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. |
| doi_str_mv | 10.1016/j.bmcl.2012.11.061 |
| format | Article |
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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.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2012.11.061</identifier><identifier>PMID: 23260346</identifier><language>eng</language><publisher>Elsevier Ltd</publisher><subject>Arteriosclerosis ; Enzymes ; Inhibitor ; Lipoproteins ; Lipoproteins (low density) ; Phospholipase ; Phospholipase A2 ; Phospholipids ; Probes ; Prostate cancer ; Proteomics ; Screening ; serine hydrolase</subject><ispartof>Bioorganic & medicinal chemistry letters, 2013-02, Vol.23 (3), p.839-843</ispartof><rights>2012 Elsevier Ltd</rights><rights>2012 Elsevier Ltd. 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Our findings thus identify both inhibitors and chemoproteomic probes that are suitable for investigating Lp-PLA2 function in biological systems.</description><subject>Arteriosclerosis</subject><subject>Enzymes</subject><subject>Inhibitor</subject><subject>Lipoproteins</subject><subject>Lipoproteins (low density)</subject><subject>Phospholipase</subject><subject>Phospholipase A2</subject><subject>Phospholipids</subject><subject>Probes</subject><subject>Prostate cancer</subject><subject>Proteomics</subject><subject>Screening</subject><subject>serine hydrolase</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><recordid>eNp9UU1r3DAQFSWh2ab9Az352IvdGUmWLSiBEPIFgR6aQi9FyPK4q8VrOZJ3If8-WjYEeslhGIb3MfAeY18RKgRU3zdVt3VjxQF5hViBwg9shVLJUkioT9gKtIKy1fLPGfuU0gYAJUj5kZ1xwRUIqVbs7y8ayS1-T4Wf1r7zS4ipsFNfLNaPIVJf2APsl-dijqGjVAwhFqOfQz4X8lNpUwrO2yVT53VIeTJqExWX_DM7HeyY6MvrPme_b64fr-7Kh5-391eXD6UTssGylwPU1IimVn2jBUpHXHMldQtac3KCix4VdFI1dT04hQgKSDoBNXQt78Q5uzj6zrtuS72jaYl2NHP0WxufTbDe_I9Mfm3-hb0RtdSqldng26tBDE87SovZ-uRoHO1EYZcM8rYG3TRcZSo_Ul0MKUUa3t4gmEMvZmMOvZhDLwbR5F6y6MdRRDmFvadokvM0Oep9zPGbPvj35C9q7pYn</recordid><startdate>20130201</startdate><enddate>20130201</enddate><creator>Nagano, Joseph M.G.</creator><creator>Hsu, Ku-Lung</creator><creator>Whitby, Landon R.</creator><creator>Niphakis, Micah J.</creator><creator>Speers, Anna E.</creator><creator>Brown, Steven J.</creator><creator>Spicer, Timothy</creator><creator>Fernandez-Vega, Virneliz</creator><creator>Ferguson, Jill</creator><creator>Hodder, Peter</creator><creator>Srinivasan, Prabhavathi</creator><creator>Gonzalez, Tara D.</creator><creator>Rosen, Hugh</creator><creator>Bahnson, Brian J.</creator><creator>Cravatt, Benjamin F.</creator><general>Elsevier Ltd</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>5PM</scope></search><sort><creationdate>20130201</creationdate><title>Selective inhibitors and tailored activity probes for lipoprotein-associated phospholipase A2</title><author>Nagano, Joseph M.G. ; 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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. 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| source | Elsevier ScienceDirect Journals Complete |
| subjects | Arteriosclerosis Enzymes Inhibitor Lipoproteins Lipoproteins (low density) Phospholipase Phospholipase A2 Phospholipids Probes Prostate cancer Proteomics Screening serine hydrolase |
| title | Selective inhibitors and tailored activity probes for lipoprotein-associated phospholipase A2 |
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