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. Epub 2010 Feb 6.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Brain / metabolism
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / metabolism*
  • Cell Line
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Esters / chemistry
  • Esters / pharmacology
  • High-Throughput Screening Assays
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / metabolism*
  • Oximes / chemistry*
  • Oximes / pharmacology*
  • Proteome / metabolism

Substances

  • Cell Cycle Proteins
  • Enzyme Inhibitors
  • Esters
  • Intracellular Signaling Peptides and Proteins
  • Neoplasm Proteins
  • Oximes
  • Proteome
  • RBBP9 protein, human