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Discovery of a New Class of Uracil Derivatives as Potential Mixed Lineage Kinase Domain-like Protein (MLKL) Inhibitors
Abstract
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- Dataset
- Dataset
- Biochemistry
- Medicine
- Cell Biology
- Pharmacology
- Immunology
- Developmental Biology
- Cancer
- Infectious Diseases
- Biological Sciences not elsewhere classified
- Chemical Sciences not elsewhere classified
- programmed cell death
- mechanism studies revealed
- highly potent compounds
- cell toxicity makes
- attractive starting point
- related disease treatments
- 66 </ b
- 56 </ b
- novel mlkl inhibitors
- related diseases
- inhibitors necroptosis
- various diseases
- uracil nucleus
- uracil derivatives
- tissue damage
- target effects
- scaffold morphing
- reaction rate
- new class
- necroptosis executor
- like protein
- fold lower
- different mode