Discovery and development of ASK1 inhibitors

Prog Med Chem. 2020:59:101-179. doi: 10.1016/bs.pmch.2020.02.001. Epub 2020 Apr 22.

Abstract

Aberrant activation of mitogen-activated protein kinases (MAPKs) like c-Jun N-terminal kinase (JNK) and p38 is an event involved in the pathophysiology of numerous human diseases. The apoptosis signal-regulating kinase 1 (ASK1) is an upstream target that gets activated only under pathological conditions and as such is a promising target for therapeutic intervention. In the first part of this review the molecular mechanisms leading to ASK1 activation and regulation will be described as well as the evidences supporting a pathogenic role for ASK1 in human disease. In the second part, an update on drug discovery efforts towards the discovery and development of ASK1-targeting therapies will be provided.

Keywords: Cell death; Endoplasmatic reticulum stress; Fibrosis; Inflammation; JNK; MAP3K; Oxidative stress; p38.

Publication types

  • Review

MeSH terms

  • Drug Development*
  • Drug Discovery*
  • Humans
  • MAP Kinase Kinase Kinase 5 / antagonists & inhibitors*
  • MAP Kinase Kinase Kinase 5 / metabolism
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*

Substances

  • Protein Kinase Inhibitors
  • Small Molecule Libraries
  • MAP Kinase Kinase Kinase 5
  • MAP3K5 protein, human