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Abstract
Metastatic cancer is considered a fatal progression of cancer worldwide. It has been shown that a key player in this scenario is the CXC chemokine receptor 2 (CXCR2). To identify novel CXCR2 antagonists, a pharmacophore model was built with the HipHop program by screening a database containing compounds which were designed based on the known structure–activity relationship (SAR) of the diarylurea series CXCR2 antagonists. Compound 1a bearing the novel skeleton was selected from database screening and subjected to the in vitro biological test which showed a moderate CXCR2 antagonist potential. With further modification and exploration of SAR, compound 1e demonstrated improved CXCR2 antagonist activity with an IC50 value of 14.8 µM. Furthermore, wound healing assay using the NCI-H1299 cell line indicated that 1e showed an excellent anti-cancer metastatic effect (72% inhibition in cell migration at 50 µg ml−1).
Highlights
Tumour metastasis has become a fatal disease progress which greatly influences the diagnosis, treatment and prognosis of2018 The Authors
To identify novel CXC chemokine receptor 2 (CXCR2) antagonists, a pharmacophore model was built with the HIPHOP program by screening a database containing compounds which were designed based on the known structure–activity relationship (SAR) of the diarylurea series CXCR2 antagonists
To explore novel hit/lead compounds as CXCR2 antagonists, we designed a set of novel scaffolds on the basis of known structure–activity relationships of diarylurea CXCR2 antagonists [14], as shown in figure 3a
Summary
Tumour metastasis has become a fatal disease progress which greatly influences the diagnosis, treatment and prognosis of2018 The Authors. Many inhibitors, including vascular endothelial growth factor receptor inhibitors [3,4], integrin inhibitors [5,6] or matrix metalloprotease (MMP) inhibitors [7], have been developed for the treatment of cancer cell metastasis. CXCR2 belongs to the G protein-coupled receptor family, which is a seven-transmembrane protein and can be activated by several ELR+ CXC chemokines, including interleukin-8 (IL-8 or CXCL8), growth-related oncogenes (GROα, β and γ), neutrophil-activating peptide and granulocyte chemotactic protein-2 [10]. Reparixin, combined with paclitaxel, has been used for the treatment of metastatic breast cancer since 2016. SX-682 is in phase I clinical trial for the treatment of metastatic melanoma, in combination with pembrolizumab
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