Identification of allosteric binding sites for PI3Kα oncogenic mutant specific inhibitor design

Bioorg Med Chem. 2017 Feb 15;25(4):1481-1486. doi: 10.1016/j.bmc.2017.01.012. Epub 2017 Jan 16.

Abstract

PIK3CA, the gene that encodes the catalytic subunit of phosphatidylinositol 3-kinase α (PI3Kα), is frequently mutated in breast and other types of cancer. A specific inhibitor that targets the mutant forms of PI3Kα could maximize treatment efficiency while minimizing side-effects. Herein we describe the identification of novel binding pockets that may provide an opportunity for the design of mutant selective inhibitors. Using a fragment-based approach, we screened a library of 352 fragments (MW<300Da) for binding to PI3Kα by X-ray crystallography. Five novel binding pockets were identified, each providing potential opportunities for inhibitor design. Of particular interest was a binding pocket near Glu542, which is located in one of the two most frequently mutated domains.

Keywords: Fragment-based drug discovery; PI3K; PIK3CA; PIP(2); PIP(3).

MeSH terms

  • Allosteric Site* / drug effects
  • Allosteric Site* / genetics
  • Class I Phosphatidylinositol 3-Kinases
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Mutant Proteins / antagonists & inhibitors*
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism*
  • Mutation
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Mutant Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human