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MARILIA BARRECA

Advances in developing noncovalent small molecules targeting Keap1

  • Autori: Barreca, Marilia; Qin, Yuting; Cadot, Marie Elodie Hélène; Barraja, Paola; Bach, Anders
  • Anno di pubblicazione: 2023
  • Tipologia: Review essay (rassegna critica)
  • OA Link: http://hdl.handle.net/10447/621286

Abstract

Kelch-like ECH-associated protein 1 (Keap1) is a drug target for diseases involving oxidative stress and inflam-mation. There are three covalent Keap1-binding drugs on the market, but noncovalent compounds that inhibit the interaction between Keap1 and nuclear factor erythroid 2 -related factor 2 (Nrf2) represent an attractive alternative. Both compound types prevent degradation of Nrf2, lead-ing to the expression of antioxidant and antiinflammatory proteins. However, their off-target profiles differ as do their exact pharmacodynamic effects. Here, we discuss the opportunities and challenges of targeting Keap1 with covalent versus noncovalent inhibitors. We then provide a comprehensive overview of current noncovalent Keap1-Nrf2 inhibitors, with a focus on their pharmacological effects, to examine the therapeutic potential for this compound class.