2. Academic Validation
  3. Oxime esters as selective, covalent inhibitors of the serine hydrolase retinoblastoma-binding protein 9 (RBBP9)

Oxime esters as selective, covalent inhibitors of the serine hydrolase retinoblastoma-binding protein 9 (RBBP9)

  • Bioorg Med Chem Lett. 2010 Apr 1;20(7):2254-8. doi: 10.1016/j.bmcl.2010.02.011.
Daniel A Bachovchin 1,  Monique R Wolfe,  Kim Masuda,  Steven J Brown,  Timothy P Spicer,  Virneliz Fernandez-Vega,  Peter Chase,  Peter S Hodder,  Hugh Rosen,  Benjamin F Cravatt
Affiliations

Affiliation

  • 1 Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd. La Jolla, CA 92037, United States.
PMID: 20207142 DOI: 10.1016/j.bmcl.2010.02.011
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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