The rational design of a novel potent analogue of the 5'-AMP-activated protein kinase inhibitor compound C with improved selectivity and cellular activity

Bioorg Med Chem Lett. 2010 Nov 15;20(22):6394-9. doi: 10.1016/j.bmcl.2010.09.088. Epub 2010 Sep 19.

Abstract

We have designed and synthesized analogues of compound C, a non-specific inhibitor of 5'-AMP-activated protein kinase (AMPK), using a computational fragment-based drug design (FBDD) approach. Synthesizing only twenty-seven analogues yielded a compound that was equipotent to compound C in the inhibition of the human AMPK (hAMPK) α2 subunit in the heterotrimeric complex in vitro, exhibited significantly improved selectivity against a subset of relevant kinases, and demonstrated enhanced cellular inhibition of AMPK.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • AMP-Activated Protein Kinases / antagonists & inhibitors*
  • Drug Design
  • Humans
  • Models, Molecular
  • Phosphorylation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • AMP-Activated Protein Kinases