Scripps VIVO scripps research logo

  • Index
  • Log in
  • Home
  • People
  • Organizations
  • Research
  • Events
Search form

Selective inhibitor of platelet-activating factor acetylhydrolases 1b2 and 1b3 that impairs cancer cell survival

Academic Article
uri icon
  • Overview
  • Identity
  • Additional Document Info
  • View All
scroll to property group menus

Overview

related to degree

  • Zuhl, Andrea M., Ph.D. in Chemistry, Scripps Research 2006 - 2012

authors

  • Chang, Jae Won
  • Zuhl, Andrea M.
  • Speers, Anna
  • Niessen, Sherry
  • Brown, S. J.
  • Mulvihill, M. M.
  • Fan, Y. C.
  • Spicer, Timothy
  • Southern, M.
  • Scampavia, Louis
  • Fernandez-Vega, V.
  • Dix, Melissa
  • Cameron, Michael
  • Hodder, Peter
  • Rosen, Hugh
  • Nomura, D. K.
  • Kwon, O.
  • Hsu, K. L.
  • Cravatt, Benjamin

publication date

  • April 2015

journal

  • ACS Chemical Biology  Journal

abstract

  • Platelet-activating factor acetylhydrolases (PAFAHs) 1b2 and 1b3 are poorly characterized serine hydrolases that form a complex with a noncatalytic protein (1b1) to regulate brain development, spermatogenesis, and cancer pathogenesis. Determining physiological substrates and biochemical functions for the PAFAH1b complex would benefit from selective chemical probes that can perturb its activity in living systems. Here, we report a class of tetrahydropyridine reversible inhibitors of PAFAH1b2/3 discovered using a fluorescence polarization-activity-based protein profiling (fluopol-ABPP) screen of the NIH 300,000+ compound library. The most potent of these agents, P11, exhibited IC50 values of ?40 and 900 nM for PAFAH1b2 and 1b3, respectively. We confirm selective inhibition of PAFAH1b2/3 in cancer cells by P11 using an ABPP protocol adapted for in situ analysis of reversible inhibitors and show that this compound impairs tumor cell survival, supporting a role for PAFAH1b2/3 in cancer.
  • Platelet-activating factor acetylhydrolases (PAFAHs) 1b2 and 1b3 are poorly characterized serine hydrolases that form a complex with a noncatalytic protein (1b1) to regulate brain development, spermatogenesis, and cancer pathogenesis. Determining physiological substrates and biochemical functions for the PAFAH1b complex would benefit from selective chemical probes that can perturb its activity in living systems. Here, we report a class of tetrahydropyridine reversible inhibitors of PAFAH1b2/3 discovered using a fluorescence polarization-activity-based protein profiling (fluopol-ABPP) screen of the NIH 300,000+ compound library. The most potent of these agents, P11, exhibited IC50 values of ∼40 and 900 nM for PAFAH1b2 and 1b3, respectively. We confirm selective inhibition of PAFAH1b2/3 in cancer cells by P11 using an ABPP protocol adapted for in situ analysis of reversible inhibitors and show that this compound impairs tumor cell survival, supporting a role for PAFAH1b2/3 in cancer.

subject areas

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • Animals
  • Brain
  • Cell Line
  • Cell Line, Tumor
  • Cell Survival
  • Drug Evaluation, Preclinical
  • Fluorescence Polarization
  • Humans
  • Inhibitory Concentration 50
  • Lung Neoplasms
  • Mice
  • Proteomics
  • Pyridines
  • Small Molecule Libraries
  • Structure-Activity Relationship
scroll to property group menus

Identity

PubMed Central ID

  • PMC4402257

International Standard Serial Number (ISSN)

  • 1554-8929

Digital Object Identifier (DOI)

  • 10.1021/cb500893q

PubMed ID

  • 25602368
scroll to property group menus

Additional Document Info

start page

  • 925

end page

  • 932

volume

  • 10

issue

  • 4

©2021 The Scripps Research Institute | Terms of Use | Powered by VIVO

  • About
  • Contact Us
  • Support