Development of a first-in-class homolog-selective, covalent NOX4 inhibitor - 20/09/26
, Sara Marchese b, 1, Marta Massari b, Carla Lima a, Lorenzo Basile b, Joana Reis b, c, Matteo Re b, Fábio G. Martins d, Sérgio F. Sousa d, e, Inês Lima f, Sofia Benfeito f, Fernanda Borges a, Andrea Mattevi b, Daniel Chavarria f, ⁎ Abstract |
The NADPH oxidase (NOX) family in humans includes seven enzymes whose main function is to produce reactive oxygen species. Because of their role in oxidative damage, these enzymes are being explored as targets for new therapies against oxidative stress-related diseases. However, their conserved catalytic core poses selective inhibition challenging. Current inhibitors suffer from low potency, cytotoxicity, assay interference, and poor selectivity. VAS2870, a covalent NOX inhibitor targeting a cysteine in the dehydrogenase (DH) domain, does not present assay interference but still shows limited selectivity, solubility, and safety. This study aimed to develop improved VAS2870-based targeted covalent inhibitors (TCIs) by designing and screening a library of cysteine-targeting compounds against NOX1, NOX2, NOX4, and NOX5. A hit compound, compound 2 , was optimized, yielding a potent, homolog-selective NOX4 inhibitor, compound 18 . Its mechanism of action was validated, demonstrating covalent binding to a cysteine residue and showing that compound binding is hindered by the presence of FAD in the DH domain.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | NADPH oxidases (NOXs) are promising therapeutic targets to treat oxidative stress-related disorders. |
• | Maleimide-containing VAS2870 derivative (compound 2 ) inhibited NOX4 and NOX5. |
• | Linker modification yielded a selective NOX4 inhibitor (compound 18 ). |
• | FAD occupancy hinders covalent binding of 18 to the dehydrogenase (DH) domain. |
• | Compound 18 may form a broader interaction network in NOX4 DH domain than in NOX2. |
Keywords : NADPH oxidases, Homolog selectivity, Targeted covalent inhibitors, Cysteine-targeting, Michael addition, Nucleophilic substitution
Plan
| ☆ | The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. |
Vol 203
Article 119844- octobre 2026 Retour au numéro
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