Synthesis and SAR of indazole-pyridine based protein kinase B/Akt inhibitors.
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.
Woods
Keith W
KW
Cancer Research, Department R47S, AP10, Abbott Laboratories, Abbott Park, IL 60064, USA. keith.w.woods@abbott.com
Fischer
John P
JP
Claiborne
Akiyo
A
Li
Tongmei
T
Thomas
Sheela A
SA
Zhu
Gui-Dong
GD
Diebold
Robert B
RB
Liu
Xuesong
X
Shi
Yan
Y
Klinghofer
Vered
V
Han
Edward K
EK
Guan
Ran
R
Magnone
Shayna R
SR
Johnson
Eric F
EF
Bouska
Jennifer J
JJ
Olson
Amanda M
AM
de Jong
Ron
R
Oltersdorf
Tilman
T
Luo
Yan
Y
Rosenberg
Saul H
SH
Giranda
Vincent L
VL
Li
Qun
Q
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
D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D051057:Proto-Oncogene Proteins c-akt