Discovery of 2-arylquinazoline derivatives as a new class of ASK1 inhibitors

Bioorg Med Chem Lett. 2018 Feb 1;28(3):400-404. doi: 10.1016/j.bmcl.2017.12.026. Epub 2017 Dec 13.

Abstract

The development of a new series of apoptosis signal-regulating kinase 1 (ASK1) inhibitors is described. Starting from purine, pyrimidine and quinazoline scaffolds identified by high throughput screening, we used tools of structure-based drug design to develop a series of potent kinase inhibitors, including 2-arylquinazoline derivatives 12 and 23, with submicromolar inhibitory activities against ASK1. Kinetic analysis demonstrated that the 2-arylquinazoline scaffold ASK1 inhibitors described herein are ATP competitive.

Keywords: Apoptosis signal-regulating kinase (ASK1); High throughput screening; Inhibitor; Kinase; Structure-based drug design.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • MAP Kinase Kinase 6 / antagonists & inhibitors
  • MAP Kinase Kinase 6 / metabolism
  • MAP Kinase Kinase Kinase 5 / antagonists & inhibitors*
  • MAP Kinase Kinase Kinase 5 / metabolism*
  • Models, Molecular
  • Molecular Structure
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry
  • Quinazolines / pharmacology*
  • Rats
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Protein Kinase Inhibitors
  • Quinazolines
  • Tumor Necrosis Factor-alpha
  • MAP Kinase Kinase Kinase 5
  • MAP3K5 protein, human
  • MAP Kinase Kinase 6