title: 2,3,5-Trisubstituted pyridines as selective AKT inhibitors. Part II: Improved drug-like properties and kinase selectivity from azaindazoles.
abstract: A novel series of AKT inhibitors containing 2,3,5-trisubstituted pyridines with novel azaindazoles as hinge binding elements are described. Among these, the 4,7-diazaindazole compound 2c has improved drug-like properties and kinase selectivity than those of indazole 1, and displays greater than 80% inhibition of GSK3beta phosphorylation in a BT474 tumor xenograft model in mice.
authors.affiliation: Oncology Medicinal Chemistry, GlaxoSmithKline,1250 S. Collegeville, Rd., Collegeville, PA 19426, United States. hong.2.lin@gsk.com
authors.forename: Hong
authors.initials: H
authors.lastname: Lin
authors.forename: Dennis S
authors.initials: DS
authors.lastname: Yamashita
authors.forename: Jin
authors.initials: J
authors.lastname: Zeng
authors.forename: Ren
authors.initials: R
authors.lastname: Xie
authors.forename: Sharad
authors.initials: S
authors.lastname: Verma
authors.forename: Juan I
authors.initials: JI
authors.lastname: Luengo
authors.forename: Nelson
authors.initials: N
authors.lastname: Rhodes
authors.forename: Shuyun
authors.initials: S
authors.lastname: Zhang
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Robell
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Choudhry
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Lai
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Minthorn
authors.forename: Kristin K
authors.initials: KK
authors.lastname: Brown
authors.forename: Dirk A
authors.initials: DA
authors.lastname: Heerding
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011725:Pyridines; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3