Dismantling the TGF-β Axis: A Critical Transition from Occupancy-based Kinase Inhibitors to Event-driven Degraders.

The TGF-β signaling pathway plays a dual role in cancer, acting as both a tumor suppressor and a potent driver of metastasis and immune evasion. Traditional TGF-β inhibitors, primarily ATP-competitive kinase blockers, have faced clinical hurdles including systemic toxicities and compensatory resistance. This review provides a medicinal chemistry-oriented perspective on the fundamental transition from occupancy-based inhibition to event-driven targeted protein degradation (TPD). We systematically analyze the chemical evolution of TGF-β modulators, highlighting how rational SAR optimization-such as linker rigidification and the selection of tissue-specific E3 ligases-enhances ternary complex stability and catalytic efficiency (DC50). Furthermore, we discuss the transformative role of artificial intelligence (AI) and molecular docking in guiding the design of next-generation bifunctional degraders, including PROTACs and LYTACs. By synthesizing cuttingedge research and clinical data, this article outlines a roadmap for dismantling the TGF-β axis, offering strategic insights for the development of more potent, selective, and safer therapeutic agents.