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Rational Design of Small Molecule Inhibitors Targeting the Rac GTPase-p67 Signaling Axis in Inflammation

2012; Elsevier BV; Volume: 19; Issue: 2 Linguagem: Inglês

10.1016/j.chembiol.2011.12.017

1879-1301

Emily E. Bosco, Sachin Kumar, Filippo Marchioni, Jacek Biesiada, Mirosław Kordos, Kathleen Szczur, Jarek Meller, William Seibel, Ariel Mizrahi, Edgar Pick, Marie–Dominique Filippi, Yi Zheng,

Immune cells in cancer

The NADPH oxidase enzyme complex, NOX2, is responsible for reactive oxygen species production in neutrophils and has been recognized as a key mediator of inflammation. Here, we have performed rational design and in silico screen to identify a small molecule inhibitor, Phox-I1, targeting the interactive site of p67phox with Rac GTPase, which is a necessary step of the signaling leading to NOX2 activation. Phox-I1 binds to p67phox with a submicromolar affinity and abrogates Rac1 binding and is effective in inhibiting NOX2-mediated superoxide production dose-dependently in human and murine neutrophils without detectable toxicity. Medicinal chemistry characterizations have yielded promising analogs and initial information of the structure-activity relationship of Phox-I1. Our studies suggest the potential utility of Phox-I class inhibitors in NOX2 oxidase inhibition and present an application of rational targeting of a small GTPase-effector interface.