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.
- 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: [email protected].
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.