title: A selective inhibitor reveals PI3Kγ dependence of T(H)17 cell differentiation.
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.
authors.affiliation: Cellzome AG, Heidelberg, Germany.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Bergamini
authors.forename: Kathryn
authors.initials: K
authors.lastname: Bell
authors.forename: Satoko
authors.initials: S
authors.lastname: Shimamura
authors.forename: Thilo
authors.initials: T
authors.lastname: Werner
authors.forename: Andrew
authors.initials: A
authors.lastname: Cansfield
authors.forename: Katrin
authors.initials: K
authors.lastname: Müller
authors.forename: Jessica
authors.initials: J
authors.lastname: Perrin
authors.forename: Christina
authors.initials: C
authors.lastname: Rau
authors.forename: Katie
authors.initials: K
authors.lastname: Ellard
authors.forename: Carsten
authors.initials: C
authors.lastname: Hopf
authors.forename: Carola
authors.initials: C
authors.lastname: Doce
authors.forename: Daniel
authors.initials: D
authors.lastname: Leggate
authors.forename: Raffaella
authors.initials: R
authors.lastname: Mangano
authors.forename: Toby
authors.initials: T
authors.lastname: Mathieson
authors.forename: Alison
authors.initials: A
authors.lastname: O'Mahony
authors.forename: Ivan
authors.initials: I
authors.lastname: Plavec
authors.forename: Faiza
authors.initials: F
authors.lastname: Rharbaoui
authors.forename: Friedrich
authors.initials: F
authors.lastname: Reinhard
authors.forename: Mikhail M
authors.initials: MM
authors.lastname: Savitski
authors.forename: Nigel
authors.initials: N
authors.lastname: Ramsden
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.forename: Gerard
authors.initials: G
authors.lastname: Drewes
authors.forename: Oliver
authors.initials: O
authors.lastname: Rausch
authors.forename: Marcus
authors.initials: M
authors.lastname: Bantscheff
authors.forename: Gitte
authors.initials: G
authors.lastname: Neubauer
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D001667:Binding, Competitive; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D058544:Class Ib Phosphatidylinositol 3-Kinase; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D015394:Molecular Structure; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D017208:Rats, Wistar; D054852:Small Molecule Libraries / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D020381:Interleukin-17; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054852:Small Molecule Libraries; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human; C546764:Pik3cg protein, mouse