title: Isoform-specific phosphoinositide 3-kinase inhibitors from an arylmorpholine scaffold.
abstract: Phosphoinositide 3-kinases (PI3-Ks) are an ubiquitous class of signaling enzymes that regulate diverse cellular processes including growth, differentiation, and motility. Physiological roles of PI3-Ks have traditionally been assigned using two pharmacological inhibitors, LY294002 and wortmannin. Although these compounds are broadly specific for the PI3-K family, they show little selectivity among family members, and the development of isoform-specific inhibitors of these enzymes has been long anticipated. Herein, we prepare compounds from two classes of arylmorpholine PI3-K inhibitors and characterize their specificity against a comprehensive panel of targets within the PI3-K family. We identify multiplex inhibitors that potently inhibit distinct subsets of PI3-K isoforms, including the first selective inhibitor of p110beta/p110delta (IC(50) p110beta=0.13 microM, p110delta=0.63 microM). We also identify trends that suggest certain PI3-K isoforms may be more sensitive to potent inhibition by arylmorpholines, thereby guiding future drug design based on this pharmacophore.
authors.affiliation: Program in Chemistry and Chemical Biology, University of California-San Francisco, San Francisco, CA 94143, USA.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Knight
authors.forename: Gary G
authors.initials: GG
authors.lastname: Chiang
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Alaimo
authors.forename: Denise M
authors.initials: DM
authors.lastname: Kenski
authors.forename: Caroline B
authors.initials: CB
authors.lastname: Ho
authors.forename: Kristin
authors.initials: K
authors.lastname: Coan
authors.forename: Robert T
authors.initials: RT
authors.lastname: Abraham
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology*; D001665:Binding Sites; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D050356:Lipid Metabolism; D009025:Morpholines / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms / Q000037:antagonists & inhibitors*; D011494:Protein Kinases / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D000077191:Wortmannin