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Updated: Nov 4, 2025

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Discovery of Selective Transforming Growth Factor β Type II Receptor Inhibitors as Antifibrosis Agents

Shohei Miwa1,2, Masahiro Yokota1, Yoshifumi Ueyama1

  • 1Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.

ACS Medicinal Chemistry Letters
|May 31, 2021
PubMed

Insights

Selective TGF-β type II receptor (TGF-βRII) inhibitors show promise for treating fibrotic skin disorders like systemic sclerosis (SSc). Compound 29 reduced collagen expression in a mouse model, suggesting a viable therapeutic strategy.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Dermatology

Background:

  • Transforming growth factor β (TGF-β) signaling is a target for treating various disorders, but achieving specificity is challenging.
  • Existing TGF-β blockers have shown potential in treating human skin fibrosis, indicating a viable therapeutic avenue for fibrotic skin conditions.

Purpose of the Study:

  • To develop selective inhibitors of TGF-β type II receptor (TGF-βRII) signaling.
  • To evaluate the efficacy of these inhibitors in preclinical models of fibrosis.

Main Methods:

  • Design and synthesis of selective TGF-βRII inhibitors.
  • In vitro functional selectivity assays.
  • In vivo testing in a mouse fibrosis model, assessing collagen type I alpha 1 chain (COL1A1) expression.

Main Results:

  • Developed selective TGF-βRII inhibitors with high functional selectivity in cell-based assays.
  • Compound 29 demonstrated significant attenuation of COL1A1 expression in a mouse fibrosis model.
  • Selective inhibition of TGF-βRII-dependent signaling proved effective in a fibrotic context.

Conclusions:

  • Selective inhibition of TGF-βRII represents a promising therapeutic strategy for fibrotic disorders.
  • Compound 29 serves as a lead candidate for further development in treating conditions like systemic sclerosis (SSc).

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