title: Discovery of pyrazolo[1,5-a]pyridines as p110α-selective PI3 kinase inhibitors.
abstract: We have made a novel series of pyrazolo[1,5-a]pyridines as PI3 kinase inhibitors, and demonstrated their selectivity for the p110α isoform over the other Class Ia PI3 kinases. We investigated the SAR around the pyrazolo[1,5-a]pyridine ring system, and found compound 5x to be a particularly potent example (p110α IC(50) 0.9nM). This compound inhibits cell proliferation and phosphorylation of Akt/PKB, a downstream marker of PI3 kinase activity, and showed in vivo activity in an HCT-116 human xenograft model.
authors.affiliation: Auckland Cancer Society Research Centre, School of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. j.kendall@auckland.ac.nz
authors.forename: Jackie D
authors.initials: JD
authors.lastname: Kendall
authors.forename: Patrick D
authors.initials: PD
authors.lastname: O'Connor
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Marshall
authors.forename: Raphaël
authors.initials: R
authors.lastname: Frédérick
authors.forename: Elaine S
authors.initials: ES
authors.lastname: Marshall
authors.forename: Claire L
authors.initials: CL
authors.lastname: Lill
authors.forename: Woo-Jeong
authors.initials: WJ
authors.lastname: Lee
authors.forename: Sharada
authors.initials: S
authors.lastname: Kolekar
authors.forename: Mindy
authors.initials: M
authors.lastname: Chao
authors.forename: Alisha
authors.initials: A
authors.lastname: Malik
authors.forename: Shuqiao
authors.initials: S
authors.lastname: Yu
authors.forename: Claire
authors.initials: C
authors.lastname: Chaussade
authors.forename: Christina
authors.initials: C
authors.lastname: Buchanan
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Rewcastle
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Baguley
authors.forename: Jack U
authors.initials: JU
authors.lastname: Flanagan
authors.forename: Stephen M F
authors.initials: SM
authors.lastname: Jamieson
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
authors.forename: Peter R
authors.initials: PR
authors.lastname: Shepherd
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites; D045744:Cell Line, Tumor; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014183:Transplantation, Heterologous
chemical_list: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D011720:Pyrazoles; D011725:Pyridines; C023666:pyridine