A selective inhibitor reveals PI3Kγ dependence of T(H)17 cell differentiation

Nat Chem Biol. 2012 Apr 29;8(6):576-82. doi: 10.1038/nchembio.957.

Abstract

We devised a high-throughput chemoproteomics method that enabled multiplexed screening of 16,000 compounds against native protein and lipid kinases in cell extracts. Optimization of one chemical series resulted in CZC24832, which is to our knowledge the first selective inhibitor of phosphoinositide 3-kinase γ (PI3Kγ) with efficacy in in vitro and in vivo models of inflammation. Extensive target- and cell-based profiling of CZC24832 revealed regulation of interleukin-17-producing T helper cell (T(H)17) differentiation by PI3Kγ, thus reinforcing selective inhibition of PI3Kγ as a potential treatment for inflammatory and autoimmune diseases.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Arthritis, Experimental / drug therapy
  • Arthritis, Experimental / immunology
  • Arthritis, Experimental / pathology
  • Binding, Competitive
  • Cell Differentiation / drug effects*
  • Cell Line
  • Cell Movement / drug effects
  • Class Ib Phosphatidylinositol 3-Kinase
  • Drug Discovery
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Humans
  • Interleukin-17 / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Molecular Structure
  • Phosphoinositide-3 Kinase Inhibitors*
  • Rats
  • Rats, Wistar
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacokinetics
  • Small Molecule Libraries / pharmacology*
  • Small Molecule Libraries / therapeutic use
  • Structure-Activity Relationship
  • T-Lymphocytes, Helper-Inducer / cytology
  • T-Lymphocytes, Helper-Inducer / drug effects*
  • T-Lymphocytes, Helper-Inducer / enzymology
  • T-Lymphocytes, Helper-Inducer / immunology

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Enzyme Inhibitors
  • Interleukin-17
  • Phosphoinositide-3 Kinase Inhibitors
  • Small Molecule Libraries
  • Class Ib Phosphatidylinositol 3-Kinase
  • PIK3CG protein, human
  • Pik3cg protein, mouse

Associated data

  • PDB/4AOF
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