title: Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors.
abstract: 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.
authors.affiliation: 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
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Zhao
authors.forename: William H
authors.initials: WH
authors.lastname: Leister
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Robinson
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Barnett
authors.forename: Deborah
authors.initials: D
authors.lastname: Defeo-Jones
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Jones
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: Joel R
authors.initials: JR
authors.lastname: Huff
authors.forename: Hans E
authors.initials: HE
authors.lastname: Huber
authors.forename: Mark E
authors.initials: ME
authors.lastname: Duggan
mesh_terms: 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
chemical_list: 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