Identification of Inhibitors of Thrombospondin 1 Activation of TGF-β

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 (<b>1</b>), is effective <i>in vivo</i> 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 (<b>36</b>) with a single chiral center, which blocks TGF-β activation (pIC₅₀ = 8.12 nM) and has a plasma half life of 1.8 h (iv).