Discovery and SAR of oxindole-pyridine-based protein kinase B/Akt inhibitors for treating cancers.
We describe a series of potent and selective oxindole-pyridine-based protein kinase B/Akt inhibitors. The most potent compound 11n in this series demonstrated an IC(50) of 0.17nM against Akt1 and more than 100-fold selectivity over other Akt isozymes. The selectivity against other protein kinases was highly dependent on the C-3 substitutions at the oxindole scaffold, with unsubstituted 9e or 3-furan-2-ylmethylene (11n) more selective and 3-(1H-pyrrol-2-yl)methylene (11f) or 3-(1H-imidazol-2-yl)methylene (11k) less selective. In a mouse xenograft model, 9d, 11f, and 11n inhibited tumor growth but with accompanying toxicity.
Zhu
Gui-Dong
GD
Cancer Research, GPRD, Abbott Laboratories, Abbott Park, IL 60064, USA. gui-dong.zhu@abbott.com
Gandhi
Viraj B
VB
Gong
Jianchun
J
Luo
Yan
Y
Liu
Xuesong
X
Shi
Yan
Y
Guan
Ran
R
Magnone
Shayna R
SR
Klinghofer
Vered
V
Johnson
Eric F
EF
Bouska
Jennifer
J
Shoemaker
Alexander
A
Oleksijew
Anatol
A
Jarvis
Ken
K
Park
Chang
C
Jong
Ron De
RD
Oltersdorf
Tilman
T
Li
Qun
Q
Rosenberg
Saul H
SH
Giranda
Vincent L
VL
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000737:chemistry*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D000078183:Oxindoles; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D007211:Indoles; D000078183:Oxindoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C022960:2-oxindole; D051057:Proto-Oncogene Proteins c-akt