Structural basis for producing selective MAP2K7 inhibitors

Bioorg Med Chem Lett. 2020 Nov 15;30(22):127546. doi: 10.1016/j.bmcl.2020.127546. Epub 2020 Sep 12.

Abstract

Mitogen-activated protein kinase kinase 7 (MAP2K7) in the c-Jun N-terminal kinase signal cascade is an attractive drug target for a variety of diseases. The selectivity of MAP2K7 inhibitors against off-target kinases is a major barrier in drug development. We report a crystal structure of MAP2K7 complexed with a potent covalent inhibitor bearing an acrylamide moiety as an electrophile, which discloses a structural basis for producing selective and potent MAP2K7 inhibitors.

Keywords: Covalent bonding inhibitor; MAP2K7; Selectivity; Structural flexibility.

MeSH terms

  • Acrylamide / chemical synthesis
  • Acrylamide / chemistry
  • Acrylamide / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • MAP Kinase Kinase 7 / antagonists & inhibitors*
  • MAP Kinase Kinase 7 / metabolism
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • Acrylamide
  • MAP Kinase Kinase 7
  • MAP2K7 protein, human