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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

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.

Original languageEnglish
Pages (from-to)228-242
Number of pages15
JournalChemistry and Biology
Volume19
Issue number2
DOIs
StatePublished - 24 Feb 2012

Funding

FundersFunder number
National Institutes of HealthR01 CA141341, T32 HL091805
National Institutes of Health
National Heart, Lung, and Blood InstituteR41HL099244
National Heart, Lung, and Blood Institute

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