Development of potent, allosteric dual Akt1 and Akt2 inhibitors with improved physical properties and cell activity.
This letter describes the development of potent, allosteric dual Akt1 and Akt2 inhibitors with improved aqueous solubility (approximately 18 mg/mL) that translates into enhanced cell activity and caspase-3 induction.
Department of Medicinal Chemistry, Technology Enabled Synthesis Group, Merck & Co., PO Box 4, West Point, PA 19486, USA. zhijian_zhao@merck.com
Zhijian
Z
Zhao
Ronald G
RG
Robinson
Stanley F
SF
Barnett
Deborah
D
Defeo-Jones
Raymond E
RE
Jones
George D
GD
Hartman
Hans E
HE
Huber
Mark E
ME
Duggan
Craig W
CW
Lindsley
D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D019073:HT29 Cells; D006801:Humans; D007700:Kinetics; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011810:Quinoxalines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012995:Solubility; D014867:Water / Q000737:chemistry
D011810:Quinoxalines; D015842:Serine Proteinase Inhibitors; D014867:Water; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3