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Chem Biol. 2012 Feb 24;19(2):228-42. doi: 10.1016/j.chembiol.2011.12.017.

Rational design of small molecule inhibitors targeting the Rac GTPase-p67(phox) signaling axis in inflammation.

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  • 1Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, Cincinnati, OH 45229, USA.

Abstract

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 p67(phox) with Rac GTPase, which is a necessary step of the signaling leading to NOX2 activation. Phox-I1 binds to p67(phox) 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.

Copyright © 2012 Elsevier Ltd. All rights reserved.

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