Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors.
This letter describes the development of two series of potent and selective allosteric Akt kinase inhibitors that display an unprecedented level of selectivity for either Akt1, Akt2 or both Akt1/Akt2. An iterative analog library synthesis approach quickly provided a highly selective Akt1/Akt2 inhibitor that induces apoptosis in tumor cells and inhibits Akt phosphorylation in vivo.
Lindsley
Craig W
CW
Department of Medicinal Chemistry, Technology Enabled Synthesis Group, Merck Research Laboratories, Merck and Co., PO Box 4, West Point, PA 19486, USA. craig_lindsley@merck.com
Zhao
Zhijian
Z
Leister
William H
WH
Robinson
Ronald G
RG
Barnett
Stanley F
SF
Defeo-Jones
Deborah
D
Jones
Raymond E
RE
Hartman
George D
GD
Huff
Joel R
JR
Huber
Hans E
HE
Duggan
Mark E
ME
D000494:Allosteric Regulation; D017209:Apoptosis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011810:Quinoxalines / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011518:Proto-Oncogene Proteins; D011810:Quinoxalines; C494918:AKT1 protein, human; C494921:AKT2 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt