title: Discovery of Highly Isoform Selective Thiazolopiperidine Inhibitors of Phosphoinositide 3-Kinase γ.
abstract: A series of high affinity second-generation thiazolopiperidine inhibitors of PI3Kγ were designed based on some general observations around lipid kinase structure. Optimization of the alkylimidazole group led to inhibitors with higher levels of PI3Kγ selectivity. Additional insights into PI3K isoform selectivity related to sequence differences in a known distal hydrophobic pocket are also described.
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Philip N
authors.initials: PN
authors.lastname: Collier
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: David
authors.initials: D
authors.lastname: Messersmith
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Le Tiran
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Upul K
authors.initials: UK
authors.lastname: Bandarage
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Christina
authors.initials: C
authors.lastname: Boucher
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Jon
authors.initials: J
authors.lastname: Come
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Cottrell
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Veronique
authors.initials: V
authors.lastname: Damagnez
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: John D
authors.initials: JD
authors.lastname: Doran
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: James P
authors.initials: JP
authors.lastname: Griffith
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Suvarna
authors.initials: S
authors.lastname: Khare-Pandit
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Elaine B
authors.initials: EB
authors.lastname: Krueger
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Ledeboer
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Ledford
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Liao
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Sudipta
authors.initials: S
authors.lastname: Mahajan
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Cameron S
authors.initials: CS
authors.lastname: Moody
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Setu
authors.initials: S
authors.lastname: Roday
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Tiansheng
authors.initials: T
authors.lastname: Wang
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Jinwang
authors.initials: J
authors.lastname: Xu
authors.affiliation: Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Alex M
authors.initials: AM
authors.lastname: Aronov
mesh_terms: D002460:Cell Line; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines; C032727:piperidine