title: Synthesis and structure-activity relationship of 3,4'-bispyridinylethylenes: discovery of a potent 3-isoquinolinylpyridine inhibitor of protein kinase B (PKB/Akt) for the treatment of cancer.
abstract: Structure-based design and synthesis of the 3,4'-bispyridinylethylene series led to the discovery of 3-isoquinolinylpyridine 13a as a potent PKB/Akt inhibitor with an IC(50) of 1.3nM against Akt1. Compound 13a shows excellent selectivity against distinct families of kinases such as tyrosine kinases and CAMK, and displays poor to marginal selectivity against closely related kinases in the AGC and CMGC families. Moreover, 13a demonstrates potent cellular activity comparable to staurosporine, with IC(50) values of 0.42 and 0.59microM against MiaPaCa-2 and the Akt1 overexpressing FL5.12-Akt1, respectively. Inhibition of phosphorylation of the Akt downstream target GSK3 was also observed in FL5.12-Akt1 cells with an EC(50) of 1.5microM. The X-ray structures of 12 and 13a in complex with PKA in the ATP-binding site were determined.
authors.affiliation: Cancer Research, GPRD, Abbott Laboratories, Abbott Park, IL 60064-6101, USA. qun.li@abbott.com
authors.forename: Qun
authors.initials: Q
authors.lastname: Li
authors.forename: Keith W
authors.initials: KW
authors.lastname: Woods
authors.forename: Sheela
authors.initials: S
authors.lastname: Thomas
authors.forename: Gui-Dong
authors.initials: GD
authors.lastname: Zhu
authors.forename: Garrick
authors.initials: G
authors.lastname: Packard
authors.forename: John
authors.initials: J
authors.lastname: Fisher
authors.forename: Tongmei
authors.initials: T
authors.lastname: Li
authors.forename: Jianchun
authors.initials: J
authors.lastname: Gong
authors.forename: Jurgen
authors.initials: J
authors.lastname: Dinges
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Song
authors.forename: Jason
authors.initials: J
authors.lastname: Abrams
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.forename: Eric F
authors.initials: EF
authors.lastname: Johnson
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
authors.forename: Xuesong
authors.initials: X
authors.lastname: Liu
authors.forename: Vered
authors.initials: V
authors.lastname: Klinghofer
authors.forename: Ron
authors.initials: R
authors.lastname: Des Jong
authors.forename: Tilman
authors.initials: T
authors.lastname: Oltersdorf
authors.forename: Vincent S
authors.initials: VS
authors.lastname: Stoll
authors.forename: Clarissa G
authors.initials: CG
authors.lastname: Jakob
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: Vincent L
authors.initials: VL
authors.lastname: Giranda
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D006860:Hydrogen Bonding; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D051057:Proto-Oncogene Proteins c-akt