发现趋化因子受体CXCR6的小分子拮抗剂，其可抑制SK-HEP-1小鼠异种移植瘤（作为肝细胞癌模型）中的肿瘤生长。
Discovery of small molecule antagonists of chemokine receptor CXCR6 that arrest tumor growth in SK-HEP-1 mouse xenografts as a model of hepatocellular carcinoma.
作者信息
Peddibhotla Satyamaheshwar, Hershberger Paul M, Jason Kirby R, Sugarman Eliot, Maloney Patrick R, Hampton Sessions E, Divlianska Daniela, Morfa Camilo J, Terry David, Pinkerton Anthony B, Smith Layton H, Malany Siobhan
机构信息
Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
出版信息
Bioorg Med Chem Lett. 2020 Feb 15;30(4):126899. doi: 10.1016/j.bmcl.2019.126899. Epub 2019 Dec 17.
The chemokine system plays an important role in mediating a proinflammatory microenvironment for tumor growth in hepatocellular carcinoma (HCC). The CXCR6 receptor and its natural ligand CXCL16 are expressed at high levels in HCC cell lines and tumor tissues and receptor expression correlates with increased neutrophils in these tissues contributing to poor prognosis in patients. Availability of pharmacologcal tools targeting the CXCR6/CXCL16 axis are needed to elucidate the mechanism whereby neutrophils are affected in the tumor environment. We report the discovery of a series of small molecules with an exo-[3.3.1]azabicyclononane core. Our lead compound 81 is a potent (EC = 40 nM) and selective orally bioavailable small molecule antagonist of human CXCR6 receptor signaling that significantly decreases tumor growth in a 30-day mouse xenograft model of HCC.
趋化因子系统在介导促炎微环境以促进肝细胞癌（HCC）肿瘤生长方面发挥着重要作用。CXCR6受体及其天然配体CXCL16在肝癌细胞系和肿瘤组织中高表达，且受体表达与这些组织中中性粒细胞增多相关，这导致患者预后不良。需要有针对CXCR6/CXCL16轴的药理学工具来阐明肿瘤环境中中性粒细胞受影响的机制。我们报告了一系列具有外式-[3.3.1]氮杂双环壬烷核心的小分子的发现。我们的先导化合物81是一种强效（EC = 40 nM）且具有口服生物利用度的人CXCR6受体信号传导选择性小分子拮抗剂，在HCC的30天小鼠异种移植模型中可显著降低肿瘤生长。
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