Department of Neurology, Laboratory of Neuro-system and Multimorbidity and State Key Laboratory of Biotherapy and Cancer Center and Institute of Respiratory Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases & Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
Eur J Med Chem. 2024 Sep 5;275:116594. doi: 10.1016/j.ejmech.2024.116594. Epub 2024 Jun 11.
Chemokine receptor 4 (CXCR4) is a subtype receptor protein of the GPCR family with a seven-transmembrane structure widely distributed in human tissues. CXCR4 is involved in diseases (e.g., HIV-1 infection), cancer proliferation and metastasis, inflammation signaling pathways, and leukemia, making it a promising drug target. Clinical trials on CXCR4 antagonists mainly focused on peptides and antibodies, with a few small molecule compounds, such as AMD11070 (2) and MSX-122 (3), showing promise in cancer treatment. This perspective discusses the structure-activity relationship (SAR) of CXCR4 and its role in diseases, mainly focusing on the SAR of CXCR4 antagonists. It also explores the standard structural features and target interactions of CXCR4 binding in different disease categories. Furthermore, it investigates various modification strategies to propose potential improvements in the effectiveness of CXCR4 drugs.
趋化因子受体 4（CXCR4）是 G 蛋白偶联受体家族的一种亚型受体蛋白，具有广泛分布于人体组织中的七跨膜结构。CXCR4 参与多种疾病（如 HIV-1 感染）、癌症增殖和转移、炎症信号通路以及白血病的发生，因此成为一种有前途的药物靶标。针对 CXCR4 拮抗剂的临床试验主要集中在肽和抗体上，少数小分子化合物，如 AMD11070（2）和 MSX-122（3），在癌症治疗方面显示出潜力。本文主要探讨了 CXCR4 的结构-活性关系（SAR）及其在疾病中的作用，重点介绍了 CXCR4 拮抗剂的 SAR。本文还探讨了 CXCR4 在不同疾病类别中与靶标相互作用的标准结构特征，并研究了各种修饰策略，以期提高 CXCR4 药物的疗效。
