title: Discovery of trans-3,4'-bispyridinylethylenes as potent and novel inhibitors of protein kinase B (PKB/Akt) for the treatment of cancer: Synthesis and biological evaluation.
abstract: A novel series of Akt/PKB inhibitors derived from a screening lead (1) has been prepared. The novel trans-3,4'-bispyridinylethylenes described herein are potent inhibitors of Akt/PKB with IC(50) values in the low double-digit nanomolar range against Akt1. Compound 2q shows excellent selectivity against distinct families of kinases such as tyrosine kinases and CAMK, and displays poor to modest selectivity against closely related kinases in the AGC and CMGC families. The cellular activities including inhibition of cell growth and phosphorylation of downstream target GSK3 are also described. The X-ray structure of compound 2q complexed with PKA in the ATP binding site was 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: Tongmei
authors.initials: T
authors.lastname: Li
authors.forename: Gui-Dong
authors.initials: GD
authors.lastname: Zhu
authors.forename: Jianchun
authors.initials: J
authors.lastname: Gong
authors.forename: Akiyo
authors.initials: A
authors.lastname: Claibone
authors.forename: Chris
authors.initials: C
authors.lastname: Dalton
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: Joy L
authors.initials: JL
authors.lastname: Bauch
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Bouska
authors.forename: Shannon
authors.initials: S
authors.lastname: Arries
authors.forename: Ron
authors.initials: R
authors.lastname: De 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: D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001665:Binding Sites; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D005030:Ethylenes / Q000138:chemical synthesis / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005030:Ethylenes; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3