The Rational Design of Selective Benzoxazepin Inhibitors of the α-Isoform of Phosphoinositide 3-Kinase Culminating in the Identification of (S)-2-((2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)oxy)propanamide (GDC-0326)

J Med Chem. 2016 Feb 11;59(3):985-1002. doi: 10.1021/acs.jmedchem.5b01483. Epub 2016 Jan 20.

Abstract

Inhibitors of the class I phosphoinositide 3-kinase (PI3K) isoform PI3Kα have received substantial attention for their potential use in cancer therapy. Despite the particular attraction of targeting PI3Kα, achieving selectivity for the inhibition of this isoform has proved challenging. Herein we report the discovery of inhibitors of PI3Kα that have selectivity over the other class I isoforms and all other kinases tested. In GDC-0032 (3, taselisib), we previously minimized inhibition of PI3Kβ relative to the other class I insoforms. Subsequently, we extended our efforts to identify PI3Kα-specific inhibitors using PI3Kα crystal structures to inform the design of benzoxazepin inhibitors with selectivity for PI3Kα through interactions with a nonconserved residue. Several molecules selective for PI3Kα relative to the other class I isoforms, as well as other kinases, were identified. Optimization of properties related to drug metabolism then culminated in the identification of the clinical candidate GDC-0326 (4).

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Benzoxepins / chemistry
  • Benzoxepins / metabolism
  • Benzoxepins / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Class I Phosphatidylinositol 3-Kinases
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Humans
  • Imidazoles / chemistry
  • Imidazoles / metabolism
  • Imidazoles / pharmacology*
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Macaca fascicularis
  • Mice
  • Microsomes, Liver / chemistry
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Molecular Structure
  • Oxazepines / chemistry
  • Oxazepines / metabolism
  • Oxazepines / pharmacology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Benzoxepins
  • GDC-0326
  • Imidazoles
  • Isoenzymes
  • Oxazepines
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • PIK3CB protein, human