Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA.
Eur J Med Chem. 2013 Nov;69:647-58. doi: 10.1016/j.ejmech.2013.09.004. Epub 2013 Sep 20.
Accumulating evidence has shown multiple roles that chemokine receptor CCR5 may play to promote the progression of several types of cancer. The mechanism of such promotion is believed to involve chronic inflammation that creates a microenvironment which enhances tumor survival. Therefore, blocking CCR5 function with an antagonist may provide a novel treatment of cancers such as prostate cancer. Currently, several CCR5 antagonists are available, but all have been optimized for their inhibitory activity on HIV-1 cellular membrane invasion process rather than inhibition on cytoplasmic signaling pathways. Thus, there is need to develop CCR5 antagonists focusing on blockage of CCR5 downstream signaling and inhibition of CCR5 related prostate cancer proliferation and progression. In this report, a pharmacophore analysis was conducted based on docking studies of several known CCR5 antagonists in a CCR5 homology model. A unique structural skeleton for CCR5 antagonist was constructed and functionalized, resulting in a new series of small molecules to be synthesized and characterized. A combination of CCR5 calcium flux inhibition, anti prostate cancer cell proliferation, basal cytotoxicity, and in vivo animal model studies were applied to screen the newly synthesized compounds. Results from this study provided a potential lead compound for future CCR5 antagonist development focusing on prostate cancer therapy.
越来越多的证据表明趋化因子受体 CCR5 可能在促进多种类型癌症的进展中发挥多种作用。这种促进的机制被认为涉及慢性炎症，它创造了一个增强肿瘤存活的微环境。因此，用拮抗剂阻断 CCR5 功能可能为前列腺癌等癌症提供一种新的治疗方法。目前，有几种 CCR5 拮抗剂可用，但它们都经过优化，以增强其对 HIV-1 细胞膜入侵过程的抑制活性，而不是抑制细胞质信号通路。因此，有必要开发专注于阻断 CCR5 下游信号和抑制 CCR5 相关前列腺癌增殖和进展的 CCR5 拮抗剂。在本报告中，根据几种已知的 CCR5 拮抗剂在 CCR5 同源模型中的对接研究进行了药效团分析。构建并功能化了 CCR5 拮抗剂的独特结构骨架，从而合成并表征了一系列新的小分子。将 CCR5 钙通量抑制、抗前列腺癌细胞增殖、基础细胞毒性和体内动物模型研究相结合，筛选新合成的化合物。这项研究的结果为未来专注于前列腺癌治疗的 CCR5 拮抗剂开发提供了一个潜在的先导化合物。
