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.
Zhao
Zhijian
Z
Department of Medicinal Chemistry, Technology Enabled Synthesis Group, Merck & Co., PO Box 4, West Point, PA 19486, USA. zhijian_zhao@merck.com
Robinson
Ronald G
RG
Barnett
Stanley F
SF
Defeo-Jones
Deborah
D
Jones
Raymond E
RE
Hartman
George D
GD
Huber
Hans E
HE
Duggan
Mark E
ME
Lindsley
Craig W
CW
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