Inês Lima Carvalho

PC7 – Inês Lima Carvalho

RISE-Health, Department of Biomedicine, Pharmacology and Therapeutics Unit, Faculty of Medicine, University of Porto, Portugal

up201904940@fc.up.pt

Bioisosteric replacement of the maleimide warhead in a selective covalent NOX4 inhibitor
Inês Lima¹, Mariana Castelôa¹, Sofia Benfeito¹, Fernanda Borges^1,2, Daniel Chavarria¹ ¹ RISE-Health, Department of Biomedicine, Pharmacology and Therapeutics Unit, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal ² RISE-Health, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre s/n, 4169-007 Porto, Portugal
Abstract Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) is one of the seven members of the NOX family and catalyzes the formation of reactive oxygen species. NOX4 has been implicated in neurodegenerative diseases (NDs), being a key player in pathological events such as ferroptosis, neuroinflammation, and protein aggregation [1]. Several small molecules have been identified as NOX inhibitors, but they usually present poor homolog selectivity, assay-interfering effects, unfavourable drug-like properties, and/or cytotoxicity. Therefore, the development of new selective, non-interfering inhibitors of NOX4 is of upmost importance to clearly understand its biological role and to validate it as a drug target for NDs [2, 3]. Recently, the team developed MAC18, a covalent, selective NOX4 inhibitor with µM potency, targeting a cysteine residue within the enzyme’s dehydrogenase domain. Structurally, MAC18 is composed of a maleimide warhead and a heterocyclic ring connected through a linker. As part of our drug discovery program, this work aims at developing MAC18 derivatives bearing maleimide bioisosteres with moderate electrophilicity for NOX inhibition screenings. Following the optimization of the synthetic strategy, a small library of compounds was successfully synthesized. The results obtained so far will be presented in this communication.
References [1] N. Boonpraman, S.S. Yi, NADPH oxidase 4 (NOX4) as a biomarker and therapeutic target in neurodegenerative diseases, Neural. Regen. Res., 19 (2024) 1961–1966. https://doi.org/10.4103/1673-5374.390973 [2] J. Reis, C. Gorgulla, M. Massari, et al., Targeting ROS production through inhibition of NADPH oxidases, Nat. Chem. Biol., 19 (2023) 1540–1550. https://doi.org/10.1038/s41589-023-01457-5 [3] J. Reis, M. Massari, S. Marchese, et al., A closer look into NADPH oxidase inhibitors: Validation and insight into their mechanism of action, Redox Biol., 32 (2020) 101466. https://doi.org/10.1016/j.redox.2020.101466 Acknowledgments This work was funded by FEDER funds through the Operational Program Competitiveness Factors COMPETE and national funds by the FCT-Foundation for Science and Technology under research grants for RISE-Health (UID/06397/2025, https://doi.org/10.54499/UID/06397/2025) and NOXIOUS (EXPL/BIA-BQM/0492/2021 – http://doi.org/10.54499/EXPL/BIA-BQM/0492/2021). This work was also funded by project IMPULSE and services of EU-OPENSCREEN (Horizon Europe: 101132028; DOI: 10.3030/101132028). M.C. (2022.13356.BD – https://doi.org/10.54499/2022.13356.BD) grant and D.C. (2024.07926.CEECIND) contract were also supported by FCT and FEDER/COMPETE funds.