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.
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.
Li
Qun
Q
Cancer Research, GPRD, Abbott Laboratories, Abbott Park, IL 60064-6101, USA. qun.li@abbott.com
Li
Tongmei
T
Zhu
Gui-Dong
GD
Gong
Jianchun
J
Claibone
Akiyo
A
Dalton
Chris
C
Luo
Yan
Y
Johnson
Eric F
EF
Shi
Yan
Y
Liu
Xuesong
X
Klinghofer
Vered
V
Bauch
Joy L
JL
Marsh
Kennan C
KC
Bouska
Jennifer J
JJ
Arries
Shannon
S
De Jong
Ron
R
Oltersdorf
Tilman
T
Stoll
Vincent S
VS
Jakob
Clarissa G
CG
Rosenberg
Saul H
SH
Giranda
Vincent L
VL
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
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