Preparation and evaluation of deconstruction analogues of 7-deoxykalafungin as AKT kinase inhibitors

Bioorg Med Chem Lett. 2014 Jan 1;24(1):271-4. doi: 10.1016/j.bmcl.2013.11.020. Epub 2013 Nov 20.

Abstract

The pyranonaphthoquinone (PNQ) lactone natural products, including 7-deoxykalafungin, have been reported to be potent and selective covalent inhibitors of AKT kinase. In this work we seek to identify structural features of the natural product scaffold that are essential for potency and selectivity. Using a deconstruction approach, we designed and prepared simplified analogues of 7-deoxykalafungin. Testing of the compounds for their ability to inhibit AKT and the closely related kinase PKA revealed that the 3,6-dihydro-2H-pyran ring of the PNQ lactones is required for potent and selective inhibition of AKT. We have also unexpectedly identified a new submicromolar inhibitor of PKA.

Keywords: 7-Deoxykalafungin; AKT kinase; Covalent inhibitor; Deconstruction analogues; Pyranonaphthoquinone lactone.

MeSH terms

  • Dose-Response Relationship, Drug
  • Molecular Structure
  • Naphthoquinones / chemical synthesis
  • Naphthoquinones / chemistry
  • Naphthoquinones / pharmacology*
  • 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

  • 7-deoxykalafungin
  • Naphthoquinones
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt