Discovery of a new class of highly potent necroptosis inhibitors targeting the mixed lineage kinase domain-like protein

Chem Commun (Camb). 2017 Mar 28;53(26):3637-3640. doi: 10.1039/c7cc00667e.

Abstract

We report the development of novel Mixed Lineage Kinase Domain-Like protein (MLKL) inhibitors with single nanomolar potency (compound 15 is also named as TC13172). Using the converting biochemistry to chemistry activity-based protein profiling (BTC-ABPP) method, we were able to determine that the inhibitors covalently bind to Cysteine86 (Cys-86) of MLKL. This is the first example of the use of LC-MS/MS to identify the binding site of an MLKL inhibitor. The novel MLKL inhibitors provide powerful tools to study the biological function of MLKL and demonstrate that MLKL should be viewed as a druggable target.

MeSH terms

  • Apoptosis / drug effects*
  • Binding Sites / drug effects
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Molecular Structure
  • Necrosis / drug therapy*
  • Necrosis / metabolism
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinases / metabolism*
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • MLKL protein, human
  • Protein Kinases