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.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Bosco
authors.forename: Sachin
authors.initials: S
authors.lastname: Kumar
authors.forename: Filippo
authors.initials: F
authors.lastname: Marchioni
authors.forename: Jacek
authors.initials: J
authors.lastname: Biesiada
authors.forename: Miroslaw
authors.initials: M
authors.lastname: Kordos
authors.forename: Kathleen
authors.initials: K
authors.lastname: Szczur
authors.forename: Jarek
authors.initials: J
authors.lastname: Meller
authors.forename: William
authors.initials: W
authors.lastname: Seibel
authors.forename: Ariel
authors.initials: A
authors.lastname: Mizrahi
authors.forename: Edgar
authors.initials: E
authors.lastname: Pick
authors.forename: Marie-Dominique
authors.initials: MD
authors.lastname: Filippi
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
mesh_terms: D048588:Benzoxazines / Q000494:pharmacology*; D001665:Binding Sites; D003198:Computer Simulation; D015195:Drug Design; D018922:HL-60 Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D009504:Neutrophils / Q000378:metabolism; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D048588:Benzoxazines; D010750:Phosphoproteins; C573130:Phox-I1; D011720:Pyrazoles; D017382:Reactive Oxygen Species; C079789:neutrophil cytosol factor 67K; D020744:rac GTP-Binding Proteins