A novel phenylcyclohex-1-enecarbothioamide derivative inhibits CXCL8-mediated chemotaxis through selective regulation of CXCR2-mediated signalling

British Journal of Pharmacology
Helen HaNouri Neamati

Abstract

Since the CXC chemokine receptor CXCR2 and its cognate ligand CXCL8 (IL-8) critically regulate neutrophil trafficking during inflammation, they have been implicated in a number of inflammatory lung diseases. Several CXCR2 antagonists have been described and the blockade of CXCR2 has shown promise in pre-clinical disease models and early clinical trials. However, given its potential, there are fewer distinct classes of antagonists of CXCR2 than of other clinically relevant molecular targets. Thus, we sought to identify additional classes of compounds that alter CXCR2 function. We used the CXCR2 Tango(TM) assay to screen an in-house library of highly diverse chemical compounds. CX4338 [2-(benzylamino)-4,4-dimethyl-6-oxo-N-phenylcyclohex-1-enecarbothioamide] was identified from our screen and additional studies to characterize the compound were performed. Receptor internalization and second-messenger assays were used to assess the effects of CX4338 on CXCR2-mediated signalling. Wound healing, transwell cell migration and LPS-induced lung inflammation in mice were used to determine the in vitro and in vivo effects of CX4338. CX4338 selectively inhibited CXCR2-mediated recruitment of β-arrestin-2 and receptor internalization, while ...Continue Reading

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Citations

Jun 24, 2017·Journal of Immunology Research·Constanza Zuñiga-TraslaviñaCarmen G Feijóo
Sep 28, 2017·American Journal of Respiratory Cell and Molecular Biology·Jordanna G JaynePaul M Beringer
Jun 5, 2014·Molecular Pharmaceutics·Helen Ha, Nouri Neamati

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