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

doi:10.1016/j.chembiol.2011.12.017

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

Clinical Microbiology and Immunology

Research output: Contribution to journal › Article › peer-review

54 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 language	English
Pages (from-to)	228-242
Number of pages	15
Journal	Chemistry and Biology
Volume	19
Issue number	2
DOIs	https://doi.org/10.1016/j.chembiol.2011.12.017
State	Published - 24 Feb 2012

Funding

Funders	Funder number
National Institutes of Health	R01 CA141341, T32 HL091805
National Institutes of Health
National Heart, Lung, and Blood Institute	R41HL099244
National Heart, Lung, and Blood Institute

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10.1016/j.chembiol.2011.12.017

Cite this

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

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.",

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

note = "Funding Information: The authors thank all members of the Zheng lab for thought-provoking discussion and acknowledge the Cincinnati Children's Hospital Medical Center (CCHMC) Biomedical Informatics computational cluster and CCHMC institutional support for assistance in the virtual screening process. The work is partly supported by National Institutes of Health grants (R41 HL099244, R01 CA141341, and T32 HL091805). The authors have no conflict of interest to declare. ",

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AU - Bosco, Emily E.

AU - Kumar, Sachin

AU - Marchioni, Filippo

AU - Biesiada, Jacek

AU - Kordos, Miroslaw

AU - Szczur, Kathleen

AU - Meller, Jarek

AU - Seibel, William

AU - Mizrahi, Ariel

AU - Pick, Edgar

AU - Filippi, Marie Dominique

AU - Zheng, Yi

N1 - Funding Information: The authors thank all members of the Zheng lab for thought-provoking discussion and acknowledge the Cincinnati Children's Hospital Medical Center (CCHMC) Biomedical Informatics computational cluster and CCHMC institutional support for assistance in the virtual screening process. The work is partly supported by National Institutes of Health grants (R41 HL099244, R01 CA141341, and T32 HL091805). The authors have no conflict of interest to declare.

PY - 2012/2/24

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N2 - 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.

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