Oxime esters as selective,covalent inhibitors of the serine hydrolase retinoblastoma-binding protein 9 (RBBP9) |
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| Authors: | Daniel A Bachovchin Monique R Wolfe Kim Masuda Steven J Brown Timothy P Spicer Virneliz Fernandez-Vega Peter Chase Peter S Hodder Hugh Rosen Benjamin F Cravatt |
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| Institution: | 1. The Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd. La Jolla, CA 92037, United States;2. The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd. La Jolla, CA 92037, United States;3. The Scripps Research Institute Molecular Screening Center, The Scripps Research Institute, 10550 N. Torrey Pines Rd. La Jolla, CA 92037, United States;4. Lead Identification Division, Molecular Screening Center, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, United States;5. Department of Molecular Therapeutics, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, United States |
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| Abstract: | We recently described a fluorescence polarization platform for competitive activity-based protein profiling (fluopol-ABPP) that enables high-throughput inhibitor screening for enzymes with poorly characterized biochemical activity. Here, we report the discovery of a class of oxime ester inhibitors for the unannotated serine hydrolase RBBP9 from a full-deck (200,000+ compound) fluopol-ABPP screen conducted in collaboration with the Molecular Libraries Screening Center Network (MLSCN). We show that these compounds covalently inhibit RBBP9 by modifying enzyme’s active site serine nucleophile and, based on competitive ABPP in cell and tissue proteomes, are selective for RBBP9 relative to other mammalian serine hydrolases. |
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