TY - JOUR
T1 - 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
AU - Camodeca, Caterina
AU - Nuti, Elisa
AU - Tepshi, Livia
AU - Boero, Silvia
AU - Tuccinardi, Tiziano
AU - Stura, Enrico A.
AU - Poggi, Alessandro
AU - Zocchi, Maria Raffaella
AU - Rossello, Armando
PY - 2016/3/23
Y1 - 2016/3/23
N2 - 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.
AB - 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.
KW - ADAM-10 inhibitors
KW - Hodgkin's lymphoma
KW - NKG2D-L
KW - Sulfonamido-based hydroxamates
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U2 - 10.1016/j.ejmech.2016.01.053
DO - 10.1016/j.ejmech.2016.01.053
M3 - Article
VL - 111
SP - 193
EP - 201
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -