PROTACs Targeting MLKL Protect Cells from Necroptosis

J Med Chem. 2023 Aug 24;66(16):11216-11236. doi: 10.1021/acs.jmedchem.3c00665. Epub 2023 Aug 3.

Abstract

Mixed Lineage Kinase domain-Like pseudokinase (MLKL) is implicated in a broad range of diseases due to its role as the ultimate effector of necroptosis and has therefore emerged as an attractive drug target. Here, we describe the development of PROteolysis TArgeting Chimeras (PROTACs) as a novel approach to knock down MLKL through chemical means. A series of candidate degraders were synthesized from a high-affinity pyrazole carboxamide-based MLKL ligand leading to the identification of a PROTAC molecule that effectively degraded MLKL and completely abrogated cell death in a TSZ model of necroptosis. By leveraging the innate ability of these PROTACs to degrade MLKL in a dose-dependent manner, the quantitative relationship between MLKL levels and necroptosis was interrogated. This work demonstrates the feasibility of targeting MLKL using a PROTAC approach and provides a powerful tool to further our understanding of the role of MLKL within the necroptotic pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Cell Death
  • Necroptosis* / drug effects
  • Protein Kinases* / metabolism
  • Proteolysis Targeting Chimera* / chemistry
  • Proteolysis Targeting Chimera* / pharmacology
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism

Substances

  • Protein Kinases
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Proteolysis Targeting Chimera
  • MLKL protein, human