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.

Barreca, M., Qin, Y., Cadot, M.E.H., Barraja, P., Bach, A. (2023). Advances in developing noncovalent small molecules targeting Keap1 [10.1016/j.drudis.2023.103800].

Advances in developing noncovalent small molecules targeting Keap1

Barreca, Marilia
Primo
;
Barraja, Paola;
2023-12-01

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.
dic-2023
Barreca, M., Qin, Y., Cadot, M.E.H., Barraja, P., Bach, A. (2023). Advances in developing noncovalent small molecules targeting Keap1 [10.1016/j.drudis.2023.103800].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10447/621286
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