Work

Identification of Inhibitors of Thrombospondin 1 Activation of TGF-β

Year: 2020

Type: article

Abstract: TGF-β has been a target of interest for the treatment of fibrotic diseases and certain cancers. Approaches to target TGF-β include antagonists of the active ligand or TGF-β receptor kinase activity. These approaches have failed in clinical trials due to a lack of effectiveness and a limited therapeutic window. In this context, newer and more selective approaches to target TGF-β are needed. We previously reported that the matricellular protein, thrombospondin 1, activates the latent TGF-β complex and that antagonism of this pathway using tri/tetrapeptides in various animal models reduces fibrosis. The tripeptide, SRI-31277 ( 1 ), is effective in vivo but has a short plasma half life (0.2 h). Herein we describe the design and synthesis SRI-31277 analogs, specifically smaller peptides that retain potency and have improved bioavailability. We identified SRI-35241 ( 36 ) with a single chiral center, which blocks TGF-β activation (pIC 50 = 8.12 nM) and has a plasma half life of 1.8 h (iv).

Source: ACS Medicinal Chemistry Letters

DOI: 10.1021/acsmedchemlett.9b00540

Authors: Mark J. Suto, Vandana Gupta, Bini Mathew, Wei Zhang, Manuel A. Pallero, Joanne E. Murphy-Ullrich

Institutions: Southern Research Institute, University of Alabama at Birmingham

Language: English

Topic: TGF-β signaling in diseases

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funders: National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases