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发现并通过计算机辅助优化新型小分子 CXCR4 拮抗剂。

Discovery and computer aided potency optimization of a novel class of small molecule CXCR4 antagonists.

机构信息

Institute of Cancer Therapeutics, University of Bradford, Bradford, United Kingdom.

出版信息

PLoS One. 2013 Oct 18;8(10):e78744. doi: 10.1371/journal.pone.0078744. eCollection 2013.

DOI:10.1371/journal.pone.0078744
PMID:24205302
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3800133/
Abstract

Amongst the chemokine signalling axes involved in cancer, chemokine CXCL12 acting on chemokine receptor CXCR4 is particularly significant since it orchestrates migration of cancer cells in a tissue-specific metastatic process. High CXCR4 tumour expression is associated with poor prognosis of lung, brain, CNS, blood and breast cancers. We have identified a new class of small molecule CXCR4 antagonists based on the use of computational modelling studies in concert with experimental determination of in vitro activity against CXCL12-induced intracellular calcium mobilisation, proliferation and chemotaxis. Molecular modelling proved to be a useful tool in rationalising our observed potencies, as well as informing the direction of the synthetic efforts aimed at producing more potent compounds.

摘要

在涉及癌症的趋化因子信号轴中，趋化因子 CXCL12 作用于趋化因子受体 CXCR4 尤为重要，因为它在组织特异性转移过程中协调癌细胞的迁移。高 CXCR4 肿瘤表达与肺癌、脑癌、中枢神经系统癌、血液癌和乳腺癌的预后不良有关。我们已经基于使用计算建模研究以及体外活性测定的协同作用，鉴定了一类新的小分子 CXCR4 拮抗剂，该测定针对 CXCL12 诱导的细胞内钙动员、增殖和趋化作用。分子建模被证明是一种有用的工具，可以合理地解释我们观察到的效力，以及为旨在产生更有效化合物的合成努力提供信息。

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The Role of chemokine receptor CXCR4 in breast cancer metastasis.趋化因子受体 CXCR4 在乳腺癌转移中的作用。
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