TY - JOUR
T1 - Rational design of small molecule inhibitors targeting the Rac GTPase-p67 phox signaling axis in inflammation
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
Y1 - 2012/2/24
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84863115260&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2011.12.017
DO - 10.1016/j.chembiol.2011.12.017
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AN - SCOPUS:84863115260
SN - 1074-5521
VL - 19
SP - 228
EP - 242
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 2
ER -