Setanaxib (GKT137831): A Comprehensive Analysis of a First-in-Class NOX1/4 Inhibitor in Fibrosis and Oncology

1.0 Executive Summary

Setanaxib (GKT137831) is an investigational, first-in-class, orally bioavailable small molecule that functions as a dual inhibitor of NADPH oxidase isoforms NOX1 and NOX4. It represents a novel therapeutic paradigm targeting the enzymatic production of reactive oxygen species (ROS), a fundamental pathological process implicated in a wide array of diseases characterized by inflammation and fibrosis.

The primary mechanism of action of setanaxib involves the selective and potent inhibition of NOX1 and NOX4. This action curtails the excessive production of ROS, thereby downregulating critical pro-fibrotic and pro-inflammatory signaling cascades, most notably the transforming growth factor-beta (TGF-$\beta$) pathway. In the context of oncology, setanaxib exhibits a distinct mechanism by targeting Cancer-Associated Fibroblasts (CAFs) within the tumor microenvironment. This targeting reverses the fibrotic, immune-exclusive barrier created by CAFs, facilitating the infiltration of cytotoxic CD8+ T-cells and enhancing the efficacy of immune checkpoint inhibitors.