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Updated: Dec 18, 2025

Visualization and Quantification of TGFβ/BMP/SMAD Signaling under Different Fluid Shear Stress Conditions using Proximity-Ligation-Assay
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Visualization and Quantification of TGFβ/BMP/SMAD Signaling under Different Fluid Shear Stress Conditions using Proximity-Ligation-Assay

Published on: September 14, 2021

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Identification of Inhibitors of Thrombospondin 1 Activation of TGF-β

Mark J Suto1, Vandana Gupta1, Bini Mathew1

  • 1Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, Alabama 35205, United States.

ACS Medicinal Chemistry Letters
|June 20, 2020
PubMed

Insights

New peptide analogs targeting transforming growth factor-beta (TGF-β) activation show promise for treating fibrosis. SRI-35241 demonstrates improved bioavailability and potency, offering a potential therapeutic advancement.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Medicinal Chemistry

Background:

  • Transforming growth factor-beta (TGF-β) is a key mediator in fibrotic diseases and cancers.
  • Previous TGF-β targeting strategies have shown limited success in clinical trials due to efficacy and safety concerns.
  • Thrombospondin 1 (TSP-1) activates latent TGF-β, presenting a novel therapeutic target.

Purpose of the Study:

  • To design and synthesize novel analogs of the tripeptide SRI-31277 with improved pharmacokinetic properties.
  • To identify selective TGF-β activation inhibitors with enhanced bioavailability and sustained therapeutic effect.

Main Methods:

  • Design and synthesis of novel tripeptide and tetrapeptide analogs.
  • Evaluation of TGF-β activation inhibition potency (pIC50) and pharmacokinetic profiling (plasma half-life).
  • Structure-activity relationship (SAR) studies to optimize peptide characteristics.

Main Results:

  • Identified SRI-35241, a novel analog with a single chiral center, as a potent inhibitor of TGF-β activation (pIC50 = 8.12 nM).
  • SRI-35241 exhibits a significantly improved plasma half-life (1.8 h) compared to SRI-31277 (0.2 h).
  • The developed analogs demonstrate retained potency with enhanced bioavailability.

Conclusions:

  • Novel peptide analogs targeting TSP-1 mediated TGF-β activation offer a promising therapeutic strategy.
  • SRI-35241 represents a lead candidate with improved pharmacokinetic profile for potential treatment of fibrotic diseases.
  • Further development of these selective TGF-β inhibitors is warranted.

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