Azole-based inhibitors of AKT/PKB for the treatment of cancer.
Through a combination of screening and structure-based rational design, we have discovered a series of N(1)-(5-(heterocyclyl)-thiazol-2-yl)-3-(4-trifluoromethylphenyl)-1,2-propanediamines that were developed into potent ATP competitive inhibitors of AKT. Studies of linker strand-binding adenine isosteres identified SAR trends in potency and selectivity that were consistent with binding interactions observed in structures of the inhibitors bound to AKT1 and to the counter-screening target PKA. One compound was shown to have acceptable pharmacokinetic properties and to be a potent inhibitor of AKT signaling and of in vivo xenograft tumor growth in a preclinical model of glioblastoma.
Zeng
Qingping
Q
Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
Allen
John G
JG
Bourbeau
Matthew P
MP
Wang
Xianghong
X
Yao
Guomin
G
Tadesse
Seifu
S
Rider
James T
JT
Yuan
Chester C
CC
Hong
Fang-Tsao
FT
Lee
Matthew R
MR
Zhang
Shiwen
S
Lofgren
Julie A
JA
Freeman
Daniel J
DJ
Yang
Suijin
S
Li
Chun
C
Tominey
Elizabeth
E
Huang
Xin
X
Hoffman
Douglas
D
Yamane
Harvey K
HK
Fotsch
Christopher
C
Dominguez
Celia
C
Hungate
Randall
R
Zhang
Xiaoling
X
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001393:Azoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001665:Binding Sites; 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; D015195:Drug Design; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001393:Azoles; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D051357:Cyclin-Dependent Kinase 2