Discovery of potent and cell-active allosteric dual Akt 1 and 2 inhibitors

Tony Siu; Jun Liang; Jeannie Arruda; Yiwei Li; Raymond E Jones; Deborah Defeo-Jones; Stanley F Barnett; Ronald G Robinson

doi:10.1016/j.bmcl.2008.05.085

Discovery of potent and cell-active allosteric dual Akt 1 and 2 inhibitors

Bioorg Med Chem Lett. 2008 Jul 15;18(14):4186-90. doi: 10.1016/j.bmcl.2008.05.085. Epub 2008 May 24.

Authors

Tony Siu¹, Jun Liang, Jeannie Arruda, Yiwei Li, Raymond E Jones, Deborah Defeo-Jones, Stanley F Barnett, Ronald G Robinson

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., 3535 General Atomics Court, San Diego, CA 92129, USA. tony_siu@merck.com

PMID: 18539456
DOI: 10.1016/j.bmcl.2008.05.085

Abstract

This paper describes the improvement of cell potency in a class of allosteric Akt 1 and 2 inhibitors. Key discoveries include identifying the solvent exposed region of the molecule and appending basic amines to enhance the physiochemical properties of the molecules. Findings from the structure-activity relationships are discussed.

MeSH terms

Allosteric Site
Chemistry, Pharmaceutical / methods
Chemistry, Physical / methods
Drug Design
Humans
Inhibitory Concentration 50
Models, Chemical
Phosphorylation
Piperazines / chemistry
Protein Kinase Inhibitors / chemistry
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
Proto-Oncogene Proteins c-akt / chemistry
Solvents / chemistry
Stereoisomerism
Structure-Activity Relationship

Substances

Piperazines
Protein Kinase Inhibitors
Solvents
Proto-Oncogene Proteins c-akt