Centre for Biomedicine and Positron Emission Tomography Research Centre, Hull York Medical School and University of Hull, Cottingham Road, Hull, HU6 7RX, UK.
The University of Manchester, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, Manchester, UK.
Dalton Trans. 2024 Mar 19;53(12):5616-5623. doi: 10.1039/d3dt01729j.
The chemokine receptor CXCR4 is implicated in multiple diseases including inflammatory disorders, cancer growth and metastasis, and HIV/AIDS. CXCR4 targeting has been evaluated in treating cancer metastasis and therapy resistance. Cyclam derivatives, most notably AMD3100 (Plerixafor™), are a common motif in small molecule CXCR4 antagonists. However, AMD3100 has not been shown to be effective in cancer treatment as an individual agent. Configurational restriction and transition metal complex formation increases receptor binding affinity and residence time. In the present study, we have synthesized novel -IV locked cyclam-based CXCR4 inhibitors, a previously unexploited configuration, and demonstrated their higher affinity for CXCR4 binding and CXCL12-mediated signaling inhibition compared to AMD3100. These results pave the way for even more potent CXCR4 inhibitors that may provide significant efficacy in cancer therapy.
趋化因子受体 CXCR4 与多种疾病有关，包括炎症性疾病、癌症的生长和转移以及艾滋病。CXCR4 靶向已被评估用于治疗癌症转移和治疗耐药性。环脒衍生物，特别是 AMD3100（plerixafor），是小分子 CXCR4 拮抗剂中的常见基序。然而，AMD3100 作为单一药物在癌症治疗中并未显示出有效性。构象限制和过渡金属配合物的形成增加了受体结合亲和力和停留时间。在本研究中，我们合成了新型的 -IV 锁定环脒基 CXCR4 抑制剂，这是以前未开发的构型，并证明它们与 AMD3100 相比，对 CXCR4 结合和 CXCL12 介导的信号抑制具有更高的亲和力。这些结果为开发更有效的 CXCR4 抑制剂铺平了道路，这些抑制剂可能在癌症治疗中具有显著疗效。
