Discovery of Potent, Efficient, and Selective Inhibitors of Phosphoinositide 3-Kinase δ through a Deconstruction and Regrowth Approach

J Med Chem. 2018 Dec 27;61(24):11061-11073. doi: 10.1021/acs.jmedchem.8b01556. Epub 2018 Dec 21.

Abstract

A deconstruction of previously reported phosphoinositide 3-kinase δ (PI3Kδ) inhibitors and subsequent regrowth led to the identification of a privileged fragment for PI3Kδ, which was exploited to deliver a potent, efficient, and selective lead series with a novel binding mode observed in the PI3Kδ crystal structure.

MeSH terms

  • Administration, Inhalation
  • Animals
  • Class Ia Phosphatidylinositol 3-Kinase / chemistry
  • Crystallography, X-Ray
  • Dogs
  • Drug Evaluation, Preclinical
  • ERG1 Potassium Channel / metabolism
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Hydrogen Bonding
  • Isoquinolines / chemistry
  • Madin Darby Canine Kidney Cells
  • Phosphoinositide-3 Kinase Inhibitors*
  • Rats
  • Structure-Activity Relationship*

Substances

  • ERG1 Potassium Channel
  • Enzyme Inhibitors
  • Isoquinolines
  • KCNH2 protein, human
  • Phosphoinositide-3 Kinase Inhibitors
  • Class Ia Phosphatidylinositol 3-Kinase
  • isoquinoline