Targeting Urokinase-type plasminogen activator receptor (uPAR) in cancer therapy: Insights from the development of small-molecule inhibitors.

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.