Discovery and SAR of spirochromane Akt inhibitors

Nicholas C Kallan; Keith L Spencer; James F Blake; Rui Xu; Justin Heizer; Josef R Bencsik; Ian S Mitchell; Susan L Gloor; Matthew Martinson; Tyler Risom; Stefan D Gross; Tony H Morales; Wen-I Wu; Guy P A Vigers; Barbara J Brandhuber; Nicholas J Skelton

doi:10.1016/j.bmcl.2011.02.073

Discovery and SAR of spirochromane Akt inhibitors

Bioorg Med Chem Lett. 2011 Apr 15;21(8):2410-4. doi: 10.1016/j.bmcl.2011.02.073. Epub 2011 Feb 18.

Authors

Nicholas C Kallan¹, Keith L Spencer, James F Blake, Rui Xu, Justin Heizer, Josef R Bencsik, Ian S Mitchell, Susan L Gloor, Matthew Martinson, Tyler Risom, Stefan D Gross, Tony H Morales, Wen-I Wu, Guy P A Vigers, Barbara J Brandhuber, Nicholas J Skelton

Affiliation

¹ Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, USA. nkallan@arraybiopharma.com

PMID: 21392984
DOI: 10.1016/j.bmcl.2011.02.073

Abstract

A novel series of spirochromane pan-Akt inhibitors is reported. SAR optimization furnished compounds with improved enzyme potencies and excellent selectivity over the related AGC kinase PKA. Attempted replacement of the phenol hinge binder provided compounds with excellent Akt enzyme and cell activities but greatly diminished selectivity over PKA.

MeSH terms

Binding Sites
Crystallography, X-Ray
Drug Evaluation, Preclinical
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
Proto-Oncogene Proteins c-akt / metabolism
Structure-Activity Relationship

Substances

Protein Kinase Inhibitors
Proto-Oncogene Proteins c-akt