2. Academic Validation
  3. Discovery of a new selective inhibitor of A Disintegrin And Metalloprotease 10 (ADAM-10) able to reduce the shedding of NKG2D ligands in Hodgkin's lymphoma cell models

Discovery of a new selective inhibitor of A Disintegrin And Metalloprotease 10 (ADAM-10) able to reduce the shedding of NKG2D ligands in Hodgkin's lymphoma cell models

  • Eur J Med Chem. 2016 Mar 23:111:193-201. doi: 10.1016/j.ejmech.2016.01.053.
Caterina Camodeca 1,  Elisa Nuti 2,  Livia Tepshi 3,  Silvia Boero 4,  Tiziano Tuccinardi 2,  Enrico A Stura 5,  Alessandro Poggi 4,  Maria Raffaella Zocchi 1,  Armando Rossello 6
Affiliations

Affiliations

  • 1 Division of Immunology, Transplants and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy.
  • 2 Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
  • 3 Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy; CEA, iBiTec-S, Service d'Ingenierie Moleculaire des Proteines, CE-Saclay, 91191 Gif sur Yvette Cedex, France.
  • 4 Unit of Molecular Oncology and Angiogenesis, IRCCS AOU San Martino-IST, 16132 Genoa, Italy.
  • 5 CEA, iBiTec-S, Service d'Ingenierie Moleculaire des Proteines, CE-Saclay, 91191 Gif sur Yvette Cedex, France.
  • 6 Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy. Electronic address: armando.rossello@farm.unipi.it.
PMID: 26871660 DOI: 10.1016/j.ejmech.2016.01.053
Abstract

Hodgkin's lymphoma (HL) is the most common malignant lymphoma in young adults in the western world. This disease is characterized by an overexpression of ADAM-10 with increased release of NKG2D ligands, involved in an impaired immune response against tumor cells. We designed and synthesized two new ADAM-10 selective inhibitors, 2 and 3 based on previously published ADAM-17 selective inhibitor 1. The most promising compound was the thiazolidine derivative 3, with nanomolar activity for ADAM-10, high selectivity over ADAM-17 and MMPs and good efficacy in reducing the shedding of NKG2D ligands (MIC-B and ULBP3) in three different HL cell lines at non-toxic doses. Molecular modeling studies were used to drive the design and X-ray crystallography studies were carried out to explain the selectivity of 3 for ADAM-10 over MMPs.

Keywords

ADAM-10 inhibitors; Hodgkin's lymphoma; NKG2D-L; Sulfonamido-based hydroxamates.

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