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

doi:10.1038/s41589-023-01457-5

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 newspaper › Journal article › Research › peer-review

11 Citations (Scopus)

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.

Original language	English
Journal	Nature Chemical Biology
Volume	19
Issue	12
Pages (from-to)	1540-1550
Number of pages	11
ISSN	1552-4450
DOIs	https://doi.org/10.1038/s41589-023-01457-5
Publication status	Published - Dec 2023
Externally published	Yes

Keywords

Cell Line
Humans
NADPH Oxidases/chemistry
Neoplasms/drug therapy
Oxidation-Reduction
Reactive Oxygen Species/metabolism

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10.1038/s41589-023-01457-5

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Reis, J., Gorgulla, C., Massari, M., Marchese, S., Valente, S., Noce, B., Basile, L., Törner, R., Cox, H., Viennet, T., Yang, M. H., Ronan, M. M., Rees, M. G., Roth, J. A., Capasso, L., Nebbioso, A., Altucci, L., Mai, A., Arthanari, H., & Mattevi, A. (2023). Targeting ROS production through inhibition of NADPH oxidases. Nature Chemical Biology, 19(12), 1540-1550. https://doi.org/10.1038/s41589-023-01457-5

@article{817285d055b84095943438ec087b7917,

title = "Targeting ROS production through inhibition of NADPH oxidases",

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.",

keywords = "Cell Line, Humans, NADPH Oxidases/chemistry, Neoplasms/drug therapy, Oxidation-Reduction, Reactive Oxygen Species/metabolism",

author = "Joana Reis and Christoph Gorgulla and Marta Massari and Sara Marchese and Sergio Valente and Beatrice Noce and Lorenzo Basile and Ricarda T{\"o}rner and Huel Cox and Thibault Viennet and Yang, {Moon Hee} and Ronan, {Melissa M.} and Rees, {Matthew G.} and Roth, {Jennifer A.} and Lucia Capasso and Angela Nebbioso and Lucia Altucci and Antonello Mai and Haribabu Arthanari and Andrea Mattevi",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2023",

month = dec,

doi = "10.1038/s41589-023-01457-5",

language = "English",

volume = "19",

pages = "1540--1550",

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Reis, J, Gorgulla, C, Massari, M, Marchese, S, Valente, S, Noce, B, Basile, L, Törner, R, Cox, H, Viennet, T, Yang, MH, Ronan, MM, Rees, MG, Roth, JA, Capasso, L, Nebbioso, A, Altucci, L, Mai, A, Arthanari, H & Mattevi, A 2023, 'Targeting ROS production through inhibition of NADPH oxidases', Nature Chemical Biology, vol. 19, no. 12, pp. 1540-1550. https://doi.org/10.1038/s41589-023-01457-5

TY - JOUR

T1 - Targeting ROS production through inhibition of NADPH oxidases

AU - Reis, Joana

AU - Gorgulla, Christoph

AU - Massari, Marta

AU - Marchese, Sara

AU - Valente, Sergio

AU - Noce, Beatrice

AU - Basile, Lorenzo

AU - Törner, Ricarda

AU - Cox, Huel

AU - Viennet, Thibault

AU - Yang, Moon Hee

AU - Ronan, Melissa M.

AU - Rees, Matthew G.

AU - Roth, Jennifer A.

AU - Capasso, Lucia

AU - Nebbioso, Angela

AU - Altucci, Lucia

AU - Mai, Antonello

AU - Arthanari, Haribabu

AU - Mattevi, Andrea

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

KW - Cell Line

KW - Humans

KW - NADPH Oxidases/chemistry

KW - Neoplasms/drug therapy

KW - Oxidation-Reduction

KW - Reactive Oxygen Species/metabolism

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U2 - 10.1038/s41589-023-01457-5

DO - 10.1038/s41589-023-01457-5

M3 - Journal article

C2 - 37884805

AN - SCOPUS:85174921719

SN - 1552-4450

VL - 19

SP - 1540

EP - 1550

JO - Nature Chemical Biology

JF - Nature Chemical Biology

IS - 12

ER -

Targeting ROS production through inhibition of NADPH oxidases

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Keywords

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