Imidazo[1,2-a]pyridine-based peptidomimetics as inhibitors of Akt

Bioorg Med Chem Lett. 2014 Oct 1;24(19):4650-4653. doi: 10.1016/j.bmcl.2014.08.040. Epub 2014 Aug 28.

Abstract

We report the design, synthesis, and biological evaluation of imidazopyridine-based peptidomimetics based on the substrate consensus sequence of Akt, an AGC family serine/threonine kinase hyperactivated in over 50% of human tumors. Our ligand-based approach led to the identification of novel substrate mimetic inhibitors of Akt1 featuring an unnatural extended dipeptide surrogate. Compound 11 inhibits Akt isoforms in the sub-micromolar range and exhibits improved proteolytic stability relative to a parent pentapeptide.

Keywords: Dipeptide surrogate; Kinase inhibitor; Peptide mimic; β-Strand mimic.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Peptidomimetics / chemical synthesis
  • Peptidomimetics / chemistry
  • Peptidomimetics / 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
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Peptidomimetics
  • Protein Kinase Inhibitors
  • Pyridines
  • Proto-Oncogene Proteins c-akt
  • imidazo(1,2-a)pyridine