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.

Targeting ROS production through inhibition of NADPH oxidases / Reis, Joana; Gorgulla, Christoph; Massari, Marta; Marchese, Sara; Valente, Sergio; Noce, Beatrice; Basile, Lorenzo; Törner, Ricarda; Cox, Huel; Viennet, Thibault; Yang, Moon Hee; Ronan, Melissa M; Rees, Matthew G; Roth, Jennifer A; Capasso, Lucia; Nebbioso, Angela; Altucci, Lucia; Mai, Antonello; Arthanari, Haribabu; Mattevi, Andrea. - In: NATURE CHEMICAL BIOLOGY. - ISSN 1552-4469. - 19:(2023), pp. 1540-1550. [10.1038/s41589-023-01457-5]

Targeting ROS production through inhibition of NADPH oxidases

Valente, Sergio;Noce, Beatrice;Mai, Antonello;
2023

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.
2023
NADPH oxidase; NOX; Reactive oxygen species, ROS scavengers; Cancer; Myeloid Leukaemia
01 Pubblicazione su rivista::01a Articolo in rivista
Targeting ROS production through inhibition of NADPH oxidases / Reis, Joana; Gorgulla, Christoph; Massari, Marta; Marchese, Sara; Valente, Sergio; Noce, Beatrice; Basile, Lorenzo; Törner, Ricarda; Cox, Huel; Viennet, Thibault; Yang, Moon Hee; Ronan, Melissa M; Rees, Matthew G; Roth, Jennifer A; Capasso, Lucia; Nebbioso, Angela; Altucci, Lucia; Mai, Antonello; Arthanari, Haribabu; Mattevi, Andrea. - In: NATURE CHEMICAL BIOLOGY. - ISSN 1552-4469. - 19:(2023), pp. 1540-1550. [10.1038/s41589-023-01457-5]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1691312
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