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Updated: Jul 8, 2026

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
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Dismantling the TGF-β Axis: A Critical Transition from Occupancy-based Kinase Inhibitors to Event-driven Degraders

Shasha Shen1, Juan Li1, Xue Cui1

  • 1Department of Head and Neck Oncology, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China.

Mini Reviews in Medicinal Chemistry
|July 7, 2026
PubMed

Insights

Targeted protein degradation (TPD) offers a novel approach to inhibiting the transforming growth factor beta (TGF-β) pathway, overcoming limitations of traditional inhibitors. This strategy promises more potent, selective, and safer cancer therapeutics.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • The transforming growth factor beta (TGF-β) signaling pathway exhibits a dual role in cancer, promoting tumor suppression in early stages but driving metastasis and immune evasion in advanced disease.
  • Conventional TGF-β inhibitors, mainly ATP-competitive kinase blockers, have encountered significant clinical challenges, including dose-limiting toxicities and the emergence of resistance mechanisms.
  • Targeted Protein Degradation (TPD) represents a paradigm shift from occupancy-based inhibition to event-driven degradation of target proteins.

Purpose of the Study:

  • To provide a medicinal chemistry perspective on the evolution of TGF-β modulators from traditional inhibitors to TPD-based strategies.
  • To analyze the chemical optimization of TGF-β modulators, focusing on enhancing ternary complex stability and catalytic efficiency.
  • To explore the role of artificial intelligence (AI) and molecular docking in designing next-generation bifunctional degraders like PROTACs and LYTACs.

Main Methods:

  • Systematic analysis of the chemical evolution of TGF-β modulators.
  • Review of structure-activity relationship (SAR) optimizations, including linker rigidification and E3 ligase selection.
  • Discussion of AI and molecular docking applications in designing bifunctional degraders.

Main Results:

  • Rational SAR optimization, including linker rigidification and tissue-specific E3 ligase selection, improves ternary complex stability and catalytic efficiency (DC50).
  • AI and molecular docking are instrumental in guiding the design of advanced bifunctional degraders (PROTACs, LYTACs).
  • The transition to TPD offers a promising avenue for overcoming the limitations of traditional TGF-β inhibitors.

Conclusions:

  • TPD strategies provide a roadmap for effectively dismantling the TGF-β signaling axis in cancer.
  • Next-generation bifunctional degraders designed using AI and advanced chemistry hold potential for developing more potent, selective, and safer TGF-β-targeted therapies.
  • This review synthesizes current research to guide future therapeutic development against TGF-β-driven cancers.
Keywords:
E3 ligasePROTACsTGF-β signalingkinase inhibitorsmedicinal chemistrymolecular gluesprecision oncology

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