Zhang Han, Xie Zhinuo, Xie Song, Wu Juhong, Khan Majid, Gao Ping, Li Jinyu
College of Chemistry, Fuzhou University, 350116 Fuzhou, China.
College of Chemistry, Fuzhou University, 350116 Fuzhou, China.
Bioorg Chem. 2025 Aug;163:108773. doi: 10.1016/j.bioorg.2025.108773. Epub 2025 Jul 20.
Cancer is characterized by the uncontrolled proliferation of cells that can invade and metastasize to distant organs, with metastasis accounting for over 90 % of cancer-related mortalities. The urokinase-type plasminogen activator receptor (uPAR), a critical hub for cancer proliferation and metastasis, angiogenesis, and inflammation, emerges as a promising anti-cancer and anti-metastasis target. Developing small-molecule inhibitors that disrupt the interaction between uPAR and its ligand, urokinase-type plasminogen activator (uPA), constitutes a major focus in anticancer drug discovery. This review collates studies on uPAR-targeted small-molecule inhibitors published over the past three decades in a comprehensive manner. We categorize the reported inhibitors by core chemical scaffolds and analyze their roles in disrupting tumor-associated angiogenesis and inflammatory signaling, to elucidate the structure-activity relationships (SAR) of these compounds against uPAR. Furthermore, we discuss current research progress, address challenges, and evaluate the potential of computer-aided drug design to accelerate uPAR inhibitor development. This review may not only pave the way for novel uPAR inhibitors but also highlights their broader therapeutic implications in modulating the tumor microenvironment.
癌症的特征是细胞不受控制地增殖，这些细胞能够侵袭并转移至远处器官，其中转移导致了超过90%的癌症相关死亡。尿激酶型纤溶酶原激活剂受体（uPAR）是癌症增殖、转移、血管生成和炎症的关键枢纽，是一个很有前景的抗癌和抗转移靶点。开发能够破坏uPAR与其配体尿激酶型纤溶酶原激活剂（uPA）之间相互作用的小分子抑制剂，是抗癌药物研发的一个主要重点。本综述全面整理了过去三十年发表的关于uPAR靶向小分子抑制剂的研究。我们根据核心化学骨架对报道的抑制剂进行分类，并分析它们在破坏肿瘤相关血管生成和炎症信号传导中的作用，以阐明这些化合物针对uPAR的构效关系（SAR）。此外，我们讨论了当前的研究进展，解决了面临的挑战，并评估了计算机辅助药物设计在加速uPAR抑制剂开发方面的潜力。本综述不仅可能为新型uPAR抑制剂铺平道路，还突出了它们在调节肿瘤微环境方面更广泛的治疗意义。
