Discovery of a New Class of Uracil Derivatives as Potential Mixed Lineage Kinase Domain-like Protein (MLKL) Inhibitors

Necroptosis is a form of programmed
cell death. Mixed lineage kinase
domain-like protein (MLKL) is the necroptosis executor, and it is
involved in various diseases such as tissue damage and neurodegeneration-related
diseases. Here, we report the development of novel MLKL inhibitors
with a uracil nucleus through scaffold morphing from our previously
reported xanthine MLKL inhibitor TC13172. After a rational structure–activity
relationship study, we obtained the highly potent compounds 56 and 66. Mechanism studies revealed that these
compounds partially inhibited MLKL oligomerization and significantly
inhibited MLKL translocation to the membrane. Compared with TC13172, 56 and 66 have a different mode of action and,
importantly, their reaction rate with glutathione is more than 150-fold
lower. This reduction in potential off-target effects and cell toxicity
makes this series an attractive starting point for further drug development
for MLKL-related disease treatments.