Identification of Inhibitors of Thrombospondin 1 Activation of TGF-β

Academic 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 (pIC50 = 8.12 nM) and has a plasma half life of 1.8 h (iv).
  • Published In

    Digital Object Identifier (doi)

    Author List

  • Suto MJ; Gupta V; Mathew B; Zhang W; Pallero MA; Murphy-Ullrich JE
  • Start Page

  • 1130
  • End Page

  • 1136
  • Volume

  • 11
  • Issue

  • 6