Identification and optimisation of a 4',5-bisthiazole series of selective phosphatidylinositol-3 kinase alpha inhibitors

Bioorg Med Chem Lett. 2015 Sep 1;25(17):3569-74. doi: 10.1016/j.bmcl.2015.06.078. Epub 2015 Jun 27.

Abstract

Exploring the affinity-pocket binding moiety of a 2-aminothiazole (S)-proline-amide-urea series of selective PI3Kα inhibitors using a parallel-synthesis approach led to the identification of a novel 4',5-bisthiazole sub-series. The synthesis and optimisation of both the affinity pocket and (S)-proline amide moieties within this 4',5-bisthiazole sub-series are described. From this work a number of analogues, including 14 (A66) and 24, were identified as potent and selective PI3Kα inhibitor in vitro tool compounds.

Keywords: Kinase inhibitor; Oncology; Phosphatidylinositol-3-kinase-alpha.

MeSH terms

  • Animals
  • Class I Phosphatidylinositol 3-Kinases
  • Humans
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Phosphatidylinositol 3-Kinases / chemistry
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphatidylinositols
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Thiazoles / chemistry*
  • Thiazoles / pharmacology*
  • Urea / analogs & derivatives*
  • Urea / pharmacology*

Substances

  • Phosphatidylinositols
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Thiazoles
  • 2-aminothiazole
  • Urea
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human