Abstract by Jie Zang

Reactive oxygen species (ROS), when produced in excessive amounts, can cause oxidative stress, which has been implicated in numerous diseases. Among the ROS-generating enzymes, the NADPH oxidases (NOX) stand out, as their sole role is to produce ROS. Here, we have used fragment-based drug discovery (FBDD) to develop new compounds that bind to the NOX2 subunit p47phox and inhibit its interaction with the p22phox subunit. This prevents assembling and activation of the multi-component NOX2 enzyme complex leading to reduced levels of superoxide and related oxidative stress. Two hits, 1 and 2, were selected for hit-to-lead elaboration using fragment growing, merging, and linking strategies. Three dimeric lead compounds (65b, 83a and 107d) with 1000-fold improved affinity (SPR, ITC, FP) were identified. Furthermore, the lead compounds showed NOX2 inhibitory activity in cell assays comparable to the currently best NOX2 specific inhibitor (GSK2795039).