Discovery of 2-pyrimidyl-5-amidothiophenes as potent inhibitors for AKT: synthesis and SAR studies.
A series of 2-pyrimidyl-5-amidothiophenes has been synthesized and evaluated for AKT inhibition. SAR studies resulted in potent inhibitors of AKT with IC(50) values as low as single digit nanomolar as represented by compound 2aa. Compound 2aa showed cellular activity including antiproliferation and downstream target modulation. Selectivity profile is described. A co-crystal of 2aa with PKA is determined and discussed.
Lin
Xiaodong
X
Small Molecule Drug Discovery, Biopharma Research, Chiron Corporation, Emeryville, CA, USA. xiaodong_lin@chiron.com
Murray
Jeremy M
JM
Rico
Alice C
AC
Wang
Michael X
MX
Chu
Daniel T
DT
Zhou
Yasheen
Y
Del Rosario
Merci
M
Kaufman
Susan
S
Ma
Sylvia
S
Fang
Eric
E
Crawford
Kenneth
K
Jefferson
A B
AB
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003460:Crystallization; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008958:Models, Molecular; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry*
D004791:Enzyme Inhibitors; D013876:Thiophenes; D051057:Proto-Oncogene Proteins c-akt