Article

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

Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Chemistry & biology (impact factor: 6.52). 02/2012; 19(2):228-42. DOI:10.1016/j.chembiol.2011.12.017 pp.228-42
Source: PubMed

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.

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Keywords

abrogates Rac1 binding
 
inflammation
 
inhibiting NOX2-mediated superoxide production dose-dependently
 
initial information
 
interactive site
 
key mediator
 
Medicinal chemistry characterizations
 
NADPH oxidase enzyme complex
 
necessary step
 
NOX2 oxidase inhibition
 
Phox-I class inhibitors
 
Phox-I1
 
Phox-I1 binds
 
potential utility
 
Rac GTPase
 
silico screen
 
small GTPase-effector interface
 
small molecule inhibitor