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

Authors

Shasha Shen, Juan Li, Xue Cui, Xiaotong Shen, Junhui Cai, Xiaoxia Gou

Published in

Mini reviews in medicinal chemistry. Jul 06, 2026. Epub Jul 06, 2026.

Abstract

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.

PMID:
42411223
Bibliographic data and abstract were imported from PubMed on 07 Jul 2026.

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