Discovery of Covalent MLKL PROTAC Degraders via Optimization of a Theophylline Derivative Ligand for Treating Necroptosis

Mixed lineage kinase domain–like
pseudokinase
(MLKL) initiates
necroptosis and could serve as a therapeutic target related to a series
of human diseases. Proteolysis-targeting chimeras (PROTACs) are useful
tools for degrading pathological proteins and blocking disease processes.
Using computer-aided modeling and molecular dynamics simulations,
we developed a series of covalent MLKL PROTACs by linking and optimizing
a theophylline derivative that covalently targets MLKL. Via structure–activity
relationship studies, MP-11 was identified as a potent
MLKL PROTAC degrader. Furthermore, MP-11 showed lower
toxicity than the original MLKL ligand, exhibiting nanomolar-scale
antinecroptotic activity on human cell lines. Xenograft model studies
showed that MP-11 effectively degraded MLKL in vivo.
Importantly, our study demonstrates that the covalent binding strategy
is an effective approach for designing MLKL-targeting PROTACs, serving
as a model for developing PROTACs to treat future necroptosis-related
human diseases.