title: Synthesis and SAR of indazole-pyridine based protein kinase B/Akt inhibitors.
abstract: A series of heteroaryl-pyridine containing inhibitors of Akt are reported. The synthesis and structure-activity relationships are discussed, leading to the discovery of a indazole-pyridine analogue (K(i)=0.16 nM). These compounds bind in the ATP binding site, are potent, ATP competitive, and reversible inhibitors of Akt activity. No selectivity amongst the Akt isoforms is observed for this analogue, but there is good selectivity against an panel of other kinases. It is least selective for other members of the AGC family of kinases but is nonetheless 40-fold selective for Akt over PKA. The compound shows cellular activity and significantly slows tumor growth in vivo.
authors.affiliation: Cancer Research, Department R47S, AP10, Abbott Laboratories, Abbott Park, IL 60064, USA. keith.w.woods@abbott.com
authors.forename: Keith W
authors.initials: KW
authors.lastname: Woods
authors.forename: John P
authors.initials: JP
authors.lastname: Fischer
authors.forename: Akiyo
authors.initials: A
authors.lastname: Claiborne
authors.forename: Tongmei
authors.initials: T
authors.lastname: Li
authors.forename: Sheela A
authors.initials: SA
authors.lastname: Thomas
authors.forename: Gui-Dong
authors.initials: GD
authors.lastname: Zhu
authors.forename: Robert B
authors.initials: RB
authors.lastname: Diebold
authors.forename: Xuesong
authors.initials: X
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
authors.forename: Vered
authors.initials: V
authors.lastname: Klinghofer
authors.forename: Edward K
authors.initials: EK
authors.lastname: Han
authors.forename: Ran
authors.initials: R
authors.lastname: Guan
authors.forename: Shayna R
authors.initials: SR
authors.lastname: Magnone
authors.forename: Eric F
authors.initials: EF
authors.lastname: Johnson
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Bouska
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Olson
authors.forename: Ron
authors.initials: R
authors.lastname: de Jong
authors.forename: Tilman
authors.initials: T
authors.lastname: Oltersdorf
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: Vincent L
authors.initials: VL
authors.lastname: Giranda
authors.forename: Qun
authors.initials: Q
authors.lastname: Li
mesh_terms: D007191:Indazoles / Q000737:chemistry*; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D051057:Proto-Oncogene Proteins c-akt