2-Aminothiadiazole inhibitors of AKT1 as potential cancer therapeutics.
A series of 2-aminothiadiazole of inhibitors of AKT1 is described. SAR relationships are discussed, along with selectivity for protein kinase A (PKA) and cyclin-dependent kinase 2 (CDK2). Moderate selectivity observed in several compounds for AKT1 versus PKA is rationalized by X-ray crystallographic analysis. Key compounds showed activity in cellular assays measuring phosphorylation of two AKT substrates, PRAS40 and FKHRL1. Compound 30 was advanced to a mouse liver PD assay, where it showed dose-dependent inhibition of AKT activity, as measured by the inhibition of phospho-PRAS40.
Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
Qingping
Q
Zeng
Matthew P
MP
Bourbeau
G Erich
GE
Wohlhieter
Guomin
G
Yao
Holger
H
Monenschein
James T
JT
Rider
Matthew R
MR
Lee
Shiwen
S
Zhang
Julie
J
Lofgren
Daniel
D
Freeman
Chun
C
Li
Elizabeth
E
Tominey
Xin
X
Huang
Douglas
D
Hoffman
Harvey
H
Yamane
Andrew S
AS
Tasker
Celia
C
Dominguez
Vellarkad N
VN
Viswanadhan
Randall
R
Hungate
Xiaoling
X
Zhang
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D013830:Thiadiazoles; D013844:Thiazoles; C004483:2-aminothiazole; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D051357:Cyclin-Dependent Kinase 2