title: 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.
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.
authors.affiliation: Division of Immunology, Transplants and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Camodeca
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Nuti
authors.affiliation: 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.
authors.forename: Livia
authors.initials: L
authors.lastname: Tepshi
authors.affiliation: Unit of Molecular Oncology and Angiogenesis, IRCCS AOU San Martino-IST, 16132 Genoa, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Boero
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Tuccinardi
authors.affiliation: CEA, iBiTec-S, Service d'Ingenierie Moleculaire des Proteines, CE-Saclay, 91191 Gif sur Yvette Cedex, France.
authors.forename: Enrico A
authors.initials: EA
authors.lastname: Stura
authors.affiliation: Unit of Molecular Oncology and Angiogenesis, IRCCS AOU San Martino-IST, 16132 Genoa, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Poggi
authors.affiliation: Division of Immunology, Transplants and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Maria Raffaella
authors.initials: MR
authors.lastname: Zocchi
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy. Electronic address: armando.rossello@farm.unipi.it.
authors.forename: Armando
authors.initials: A
authors.lastname: Rossello
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006689:Hodgkin Disease / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; C527085:KLRK1 protein, human; D008024:Ligands; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human
keywords: ADAM-10 inhibitors; Hodgkin's lymphoma; NKG2D-L; Sulfonamido-based hydroxamates