Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors

Craig W Lindsley; Zhijian Zhao; William H Leister; Ronald G Robinson; Stanley F Barnett; Deborah Defeo-Jones; Raymond E Jones; George D Hartman; Joel R Huff; Hans E Huber; Mark E Duggan

doi:10.1016/j.bmcl.2004.11.011

Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors

Bioorg Med Chem Lett. 2005 Feb 1;15(3):761-4. doi: 10.1016/j.bmcl.2004.11.011.

Authors

Craig W Lindsley¹, Zhijian Zhao, William H Leister, Ronald G Robinson, Stanley F Barnett, Deborah Defeo-Jones, Raymond E Jones, George D Hartman, Joel R Huff, Hans E Huber, Mark E Duggan

Affiliation

¹ 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

PMID: 15664853
DOI: 10.1016/j.bmcl.2004.11.011

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.

MeSH terms

Allosteric Regulation*
Apoptosis / drug effects
Enzyme Inhibitors / chemical synthesis*
Humans
Inhibitory Concentration 50
Isoenzymes / antagonists & inhibitors
Phosphorylation / drug effects
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins / antagonists & inhibitors*
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins c-akt
Quinoxalines / chemical synthesis
Quinoxalines / pharmacology
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Isoenzymes
Proto-Oncogene Proteins
Quinoxalines
AKT1 protein, human
AKT2 protein, human
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins c-akt