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Covalent Inhibitors of KEAP1 with Exquisite Selectivity.

Imre Fejes1, Piroska Markacz1, Janos Tatai1

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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.

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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.