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Covalent Inhibitors of KEAP1 with Exquisite Selectivity
Imre Fejes1, Piroska Markacz1, Janos Tatai1
1Servier Research Institute of Medicinal Chemistry, Zahony u. 7., H-1031 Budapest, Hungary.
Journal of Medicinal Chemistry
|November 21, 2024
Summary
Researchers developed novel, highly selective covalent inhibitors targeting the NRF2-KEAP1 pathway for cytoprotection. These compounds show potent in vitro and in vivo activity without genotoxicity, offering a safer therapeutic approach.
Area of Science:
- Biochemistry
- Pharmacology
- Drug Discovery
Background:
- The NRF2-KEAP1 pathway is crucial for cellular defense against oxidative stress, making it a significant therapeutic target.
- Current covalent inhibitors of KEAP1 (Kelch-like ECH-associated protein 1) lack selectivity, leading to potential side effects.
Purpose of the Study:
- To identify and optimize novel covalent inhibitors of KEAP1 with improved selectivity and reduced toxicity.
- To investigate the mechanism of action and selectivity profile of the developed compounds.
Main Methods:
- Phenotypic screening to identify initial hit compounds.
- Structure-activity relationship studies for chemical optimization.
- In vitro and in vivo assays to evaluate cellular and organismal activity.
- Genotoxicity assays.
- Activity-based protein profiling (ABPP).
- X-ray crystallography to determine the binding mode.
Main Results:
- A new chemotype of covalent KEAP1 inhibitors was discovered and optimized.
- The lead compound demonstrated potent cellular and in vivo efficacy, upregulating antioxidant response element (ARE)-dependent genes.
- No genotoxicity was observed in vitro.
- The lead compound showed broad selectivity in ABPP and minimal off-target interactions with common receptors and kinases.
- X-ray crystallography elucidated the specific interaction with KEAP1 and the basis for selectivity.
Conclusions:
- Novel, highly selective covalent KEAP1 inhibitors were successfully developed.
- These inhibitors offer a promising therapeutic strategy for stress-related conditions with an improved safety profile.
- Structural insights provide a foundation for further drug design targeting the NRF2-KEAP1 pathway.
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