A selective inhibitor reveals PI3Kγ dependence of TH17 cell differentiation

A chemoproteomic approach adapted for high-throughput screening leads to the identification of a selective PI3Kγ inhibitor. Application of this inhibitor in human and mouse cellular models reveals a role for PI3Kγ in T H 17 cell differentiation. 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.