PROTACs Targeting MLKL Protect Cells from Necroptosis

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.