title: Novel purine and pyrazolo[3,4-d]pyrimidine inhibitors of PI3 kinase-alpha: Hit to lead studies.
abstract: Series of purine and pyrazolo[3,4-d]pyrimidine inhibitors of phosphatidylinositol-3-kinases (PI3K) have been prepared. The optimized purine inhibitors show good potency in a PI3K p110alpha (PI3K-alpha) fluorescence polarization assay with good selectivity versus PI3K p110gamma (PI3K-gamma) and the mammalian target of rapamycin (mTOR). The related pyrazolo[3,4-d]pyrimidines show potent PI3K-alpha and mTOR inhibition with good selectivity versus PI3K-gamma. Representative compounds showed activity in a cellular proliferation assay against Caco-2 colorectal, LoVo colorectal and PC3MM2 prostate adenocarcinoma cancer cells. Signaling through the PI3K pathway was confirmed via inhibition of phospho-AKT in MDA-361 cells.
authors.affiliation: Medicinal Chemistry, Chemical Sciences, Wyeth Research, Pearl River, NY 10965, USA. gilbera@wyeth.com
authors.forename: Adam M
authors.initials: AM
authors.lastname: Gilbert
authors.forename: Pawel
authors.initials: P
authors.lastname: Nowak
authors.forename: Natasja
authors.initials: N
authors.lastname: Brooijmans
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Bursavich
authors.forename: Christoph
authors.initials: C
authors.lastname: Dehnhardt
authors.forename: Efren Delos
authors.initials: ED
authors.lastname: Santos
authors.forename: Larry R
authors.initials: LR
authors.lastname: Feldberg
authors.forename: Irwin
authors.initials: I
authors.lastname: Hollander
authors.forename: Stephen
authors.initials: S
authors.lastname: Kim
authors.forename: Sabrina
authors.initials: S
authors.lastname: Lombardi
authors.forename: Kaapjoo
authors.initials: K
authors.lastname: Park
authors.forename: Aranapakam M
authors.initials: AM
authors.lastname: Venkatesan
authors.forename: Robert
authors.initials: R
authors.lastname: Mallon
mesh_terms: D001665:Binding Sites; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D016231:Fluorescence Polarization Immunoassay; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011687:Purines; D011720:Pyrazoles; D011725:Pyridines; D058570:TOR Serine-Threonine Kinases; C118531:pyrazolopyridine; C546842:MTOR protein, human