Discovery of spirocyclic sulfonamides as potent Akt inhibitors with exquisite selectivity against PKA

Bioorg Med Chem Lett. 2011 Apr 15;21(8):2335-40. doi: 10.1016/j.bmcl.2011.02.098. Epub 2011 Feb 26.

Abstract

We describe the design and synthesis of novel bicyclic spiro sulfonamides as potent Akt inhibitors. Through structure-based rational design, we have successfully improved PKA selectivity of previously disclosed spirochromanes. Representative compounds showed favorable Akt potency while exhibiting up to 1000-fold selectivity against PKA.

MeSH terms

  • Binding Sites
  • Computer Simulation
  • Crystallography, X-Ray
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • 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
  • Spiro Compounds / chemistry*
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacology

Substances

  • Protein Kinase Inhibitors
  • Spiro Compounds
  • Sulfonamides
  • Proto-Oncogene Proteins c-akt
  • Cyclic AMP-Dependent Protein Kinases