@article {Lehmann410, author = {D. M. Lehmann and A. M. P. B. Seneviratne and A. V. Smrcka}, title = {Small Molecule Disruption of G Protein βγ Subunit Signaling Inhibits Neutrophil Chemotaxis and Inflammation}, volume = {73}, number = {2}, pages = {410--418}, year = {2008}, doi = {10.1124/mol.107.041780}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {G protein βγ subunit-dependent signaling is important for chemoattractant-dependent leukocyte chemotaxis. Selective small molecule targeting of phosphoinositide 3-kinase (PI3-kinase) γ catalytic activity is a target of interest for anti-inflammatory pharmaceutical development. In this study, we examined whether small-molecule inhibition of Gβγ-dependent signaling, including Gβγ-dependent activation of PI3-kinase γ and Rac1, could inhibit chemoattractant-dependent neutrophil migration in vitro and inflammation in vivo. Small-molecule Gβγ inhibitors suppressed fMLP-stimulated Rac activation, superoxide production, and PI3-kinase activation in differentiated HL60 cells. These compounds also blocked fMLP-dependent chemotaxis in HL60 cells and primary human neutrophils. Systemic administration inhibited paw edema and neutrophil infiltration in a mouse carrageenan-induced paw edema model. Overall, the data demonstrate that targeting Gβγ-regulation may be an effective anti-inflammation strategy. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/73/2/410}, eprint = {https://molpharm.aspetjournals.org/content/73/2/410.full.pdf}, journal = {Molecular Pharmacology} }