title: Structural basis for isoform selectivity in a class of benzothiazole inhibitors of phosphoinositide 3-kinase γ.
abstract: Phosphoinositide 3-kinase γ (PI3Kγ) is an attractive target to potentially treat a range of disease states. Herein, we describe the evolution of a reported phenylthiazole pan-PI3K inhibitor into a family of potent and selective benzothiazole inhibitors. Using X-ray crystallography, we discovered that compound 22 occupies a previously unreported hydrophobic binding cleft adjacent to the ATP binding site of PI3Kγ, and achieves its selectivity by exploiting natural sequence differences among PI3K isoforms in this region.
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Philip N
authors.initials: PN
authors.lastname: Collier
authors.forename: Gabriel
authors.initials: G
authors.lastname: Martinez-Botella
authors.forename: Mark
authors.initials: M
authors.lastname: Cornebise
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Cottrell
authors.forename: John D
authors.initials: JD
authors.lastname: Doran
authors.forename: James P
authors.initials: JP
authors.lastname: Griffith
authors.forename: Sudipta
authors.initials: S
authors.lastname: Mahajan
authors.forename: François
authors.initials: F
authors.lastname: Maltais
authors.forename: Cameron S
authors.initials: CS
authors.lastname: Moody
authors.forename: Emilie Porter
authors.initials: EP
authors.lastname: Huck
authors.forename: Tiansheng
authors.initials: T
authors.lastname: Wang
authors.forename: Alex M
authors.initials: AM
authors.lastname: Aronov
mesh_terms: D052160:Benzothiazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; 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; D015394:Molecular Structure; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human; C005465:benzothiazole