Targeting ROS production through inhibition of NADPH oxidases

Joana Reis, Christoph Gorgulla, Marta Massari, Sara Marchese, Sergio Valente, Beatrice Noce, Lorenzo Basile, Ricarda Törner, Huel Cox, Thibault Viennet, Moon Hee Yang, Melissa M. Ronan, Matthew G. Rees, Jennifer A. Roth, Lucia Capasso, Angela Nebbioso, Lucia Altucci, Antonello Mai*, Haribabu Arthanari*, Andrea Mattevi*

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Abstract

NADPH oxidases (NOXs) are transmembrane enzymes that are devoted to the production of reactive oxygen species (ROS). In cancers, dysregulation of NOX enzymes affects ROS production, leading to redox unbalance and tumor progression. Consequently, NOXs are a drug target for cancer therapeutics, although current therapies have off-target effects: there is a need for isoenzyme-selective inhibitors. Here, we describe fully validated human NOX inhibitors, obtained from an in silico screen, targeting the active site of Cylindrospermum stagnale NOX5 (csNOX5). The hits are validated by in vitro and in cellulo enzymatic and binding assays, and their binding modes to the dehydrogenase domain of csNOX5 studied via high-resolution crystal structures. A high-throughput screen in a panel of cancer cells shows activity in selected cancer cell lines and synergistic effects with KRAS modulators. Our work lays the foundation for the development of inhibitor-based methods for controlling the tightly regulated and highly localized ROS sources. [Figure not available: see fulltext.]

Original languageEnglish
JournalNature Chemical Biology
Volume19
Issue12
Pages (from-to)1540-1550
Number of pages11
ISSN1552-4450
DOIs
Publication statusPublished - Dec 2023
Externally publishedYes

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