Identification of novel PI3K inhibitors through a scaffold hopping strategy

Bioorg Med Chem Lett. 2017 Nov 1;27(21):4794-4799. doi: 10.1016/j.bmcl.2017.09.059. Epub 2017 Sep 30.

Abstract

A scaffold hopping strategy, including intellectual property availability assessment, was successfully applied for the discovery of novel PI3K inhibitors. Compounds were designed based on the chemical structure of the lead compound ETP-46321, a potent PI3K inhibitor, previously reported by our group. The new generated compounds showed good in vitro potency and selectivity, proved to inhibit potently the phosphorylation of AKTSer473 in cells and demonstrated to be orally bioavailable, thus becoming potential back-up candidates for ETP-46321.

Keywords: Back-up; ETP-46321; PI3K inhibitors; Scaffold hopping.

MeSH terms

  • Administration, Oral
  • Animals
  • Chemistry, Pharmaceutical
  • Drug Evaluation, Preclinical
  • Half-Life
  • Imidazoles / chemistry
  • Imidazoles / metabolism
  • Inhibitory Concentration 50
  • Mice
  • Mice, Inbred BALB C
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Phosphorylation
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyrazines / chemistry
  • Pyrazines / metabolism
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • ETP-46321
  • Imidazoles
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Isoforms
  • Protein Kinase Inhibitors
  • Pyrazines
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases