Delving into the Latest Updates on NOX2/MAOB inhibitors(Sapienza University of Rome) with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Compound 9a(Sapienza University of Rome)

Target

CYBB x MAO-B

Action

inhibitors

Mechanism

CYBB inhibitors(Cytochrome b-245 heavy chain inhibitors), MAO-B inhibitors(Monoamine oxidase B inhibitors)

Therapeutic Areas

NeoplasmsNervous System DiseasesOther Diseases

Active Indication

NeoplasmsNeurodegenerative DiseasesNeuroinflammation

Inactive Indication-

Originator Organization

Sapienza University of Rome

Active Organization

Sapienza University of Rome

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Author: Mormino, Alessandro ; Binda, Claudia ; Gottinger, Andrea ; Reis, Joana ; Mattevi, Andrea ; Limatola, Cristina ; Valente, Sergio ; Castelôa, Mariana ; Lambona, Chiara ; Fioravanti, Rossella ; Marchese, Sara ; Noce, Beatrice ; Garofalo, Stefano ; Mai, Antonello ; Fiorentino, Francesco ; Massari, Marta ; Raucci, Alessia ; Basile, Lorenzo

NADPH oxidases (NOXs) are enzymes dedicated to reactive oxygen species (ROS) production and are implicated in cancer, neuroinflammation, and neurodegenerative diseases. VAS2870 is a covalent inhibitor of mainly NOX2 and NOX5. It alkylates a conserved active-site cysteine, blocking productive substrate binding. To enhance potency and selectivity toward NOXs, we conducted some chemical modifications, leading to the discovery of compound 9a that preferentially inhibits NOX2 with an IC₅₀ of 0.155 μM, and only upon its preactivation. We found that 9a, bearing a pargyline moiety, is also able to selectively inhibit MAOB over MAOA (465-fold) with an IC₅₀ of 0.182 μM, being the first-in-class dual NOX2/MAOB covalent inhibitor. Tested in the BV2 microglia neuroinflammation model, 9a decreased ROS production and downregulated proinflammatory cytokines as iNOS, IL-1β, and IL-6 expression more efficiently than the single target inhibitors (rasagiline for MAOB and VAS2870 for NOXs) but also, more importantly, than their combination.

100 Deals associated with NOX2/MAOB inhibitors(Sapienza University of Rome)

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	Italy	Sapienza University of Rome	05 Mar 2025
Neurodegenerative Diseases	Preclinical	Italy	Sapienza University of Rome	05 Mar 2025
Neuroinflammation	Preclinical	Italy	Sapienza University of Rome	05 Mar 2025