I guess that Tioma and Forty Seven could be looking for agonists as well as blocking agents??......
J Med Chem. 2016 Sep 2. [Epub ahead of print]
Thrombospondin-1 Mimetic Agonist Peptides Induce Selective Death in Tumor Cells: Design, Synthesis, and Structure-Activity Relationship Studies.
Denèfle T1,2,3, Boullet H1,2, Herbi L4,5,6, Newton C1,2,3, Martinez-Torres AC4,5,6, Guez A1,2, Pramil E1,2,4,5,6, Quiney C4,5,6, Pourcelot M1,2,3, Levasseur MD1,2,3, Lardé E1,2,3, Moumné R1,2, Ogi FX7, Grondin P8, Merle-Beral H4,5,9, Lequin O1,2, Susin SA4,5,6, Karoyan P1,2,3.
1Sorbonne Universités, UPMC Université Paris 06, Ecole Normale Supérieure, CNRS, Laboratoire des Biomolécules, 75005 Paris, France.
2Département de Chimie, Ecole Normale Supérieure, PSL Research University, UPMC Université Paris 06, CNRS, Laboratoire des Biomolécules, 75005 Paris, France.
3UPMC Université Paris 06, Laboratoire des BioMolécules, Site GSK, 25-27 Avenue du Québec, 91140 Les Ulis, France.
4Cell Death and Drug Resistance in Lymphoproliferative Disorders Team, Centre de Recherche des Cordeliers, INSERM UMRS, 1138, Paris, France.
5Sorbonne Universités, UPMC Université Paris 06, UMRS 1138, Paris, France.
6Université Paris Descartes, Sorbonne Paris Cité, UMRS 1138, Paris, France.
7NanoTemper Technologies GmbH, Floessergasse 4, 81369 Munich, Germany.
8GSK, 25 Avenue du Québec, 91140 Les Ulis, France.
9AP-HP, GH Pitié-Salpêtrière, Service d'Hématologie Biologique, 75013 Paris, France.
Thrombospondin-1 (TSP-1) is a glycoprotein considered as a key actor within the tumor microenvironment. Its binding to CD47, a cell surface receptor, triggers programmed cell death. Previous studies allowed the identification of 4N1K decapeptide derived from the TSP-1/CD47 binding epitope. Here, we demonstrate that this peptide is able to induce selective apoptosis of various cancer cell lines while sparing normal cells. A structure-activity relationship study led to the design of the first serum stable TSP-1 mimetic agonist peptide able to trigger selective programmed cell death (PCD) of at least lung, breast, and colorectal cancer cells. Altogether, these results will be of valuable interest for further investigation in the design of potent CD47 agonist peptides, opening new perspectives for the development of original anticancer therapies. |
