Targeting Angiogenesis in Drug Discovery: Current Status and Future Directions.

Angiogenesis, the formation of new blood vessels from pre-existing vasculature, is essential for development, tissue repair, and reproduction; however, dysregulation of angiogenesis contributes to cancer, ocular disorders, chronic inflammation, and cardiovascular diseases. Current antiangiogenic therapies that target VEGF/VEGFR signalling, tyrosine kinase pathways, or utilize monoclonal antibodies have improved clinical outcomes; however, their benefits remain limited by acquired resistance, transient efficacy, and treatment-associated toxicities. This review outlines the key molecular regulators of angiogenesis, including VEGF, FGF, PDGF, Ang/Tie, and HIF-mediated hypoxic signalling, and their interactions with the immune and stromal components of the microenvironment. It further summarizes the clinical landscape of approved antiangiogenic agents, highlighting gaps in response durability, lack of predictive biomarkers, and suboptimal patient selection. Emerging strategies, such as multi-target inhibitors, modulation of the tumour microenvironment, gene-based therapies, and advanced nanotechnology-enabled delivery systems, offer opportunities to enhance therapeutic precision and overcome resistance. Artificial intelligence-driven models integrating histology and multi-omics are reshaping personalized treatment selection and trial design. This review provides a roadmap for progressing from broad antiangiogenic therapy to mechanismdriven, biomarker-guided vascular medicine, while also considering pro-angiogenic approaches for regenerative applications.