Open AccessIdentification of Inhibitors of Thrombospondin 1 Activation of TGF-β
Author(s) -
Mark J. Suto,
Vandana V. Gupta,
Biji Mathew,
Wei Zhang,
Manuel A. Pallero,
Joanne E. Murphy-Ullrich
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00540
Subject(s) - thrombospondin 1 , transforming growth factor , context (archaeology) , matricellular protein , in vivo , cancer research , pharmacology , chemistry , medicine , computational biology , biology , extracellular matrix , biochemistry , angiogenesis , paleontology , microbiology and biotechnology
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).