Activated leukocyte cell adhesion molecule (ALCAM) plays a relevant role in tumor biology and progression. Our previous studies showed that ALCAM is expressed at the surface of epithelial ovarian cancer (EOC) cells and is released in a soluble form by ADAM-17-mediated shedding. This process is relevant toEOC cell motility and invasiveness, which is reduced by nonspecific inhibitors ofADAM-17. For this reason, ADAM-17 may represent a new useful target in anticancer therapy. Herein, we report the synthesis and biological evaluation of new ADAM-17 inhibitors containing an arylsulfonamidic scaffold. Among the new potential inhibitors, two very promising compounds 17 and 18 were discovered, with a nanomolar activity for ADAM-17 isolated enzyme. These compounds proved to be also the most potent in inhibiting soluble ALCAM release in cancer cells, showing a nanomolar activity on A2774 and SKOV3 cell lines.

Potent Arylsulfonamide Inhibitors of Tumor Necrosis Factor-a Converting Enzyme Able to Reduce Activated Leukocyte Cell Adhesion Molecule Shedding in Cancer Cell Models

NUTI, ELISA;CERCIGNANI, GIOVANNI;ORLANDINI, ELISABETTA;NENCETTI, SUSANNA;ROSSELLO, ARMANDO
2010

Abstract

Activated leukocyte cell adhesion molecule (ALCAM) plays a relevant role in tumor biology and progression. Our previous studies showed that ALCAM is expressed at the surface of epithelial ovarian cancer (EOC) cells and is released in a soluble form by ADAM-17-mediated shedding. This process is relevant toEOC cell motility and invasiveness, which is reduced by nonspecific inhibitors ofADAM-17. For this reason, ADAM-17 may represent a new useful target in anticancer therapy. Herein, we report the synthesis and biological evaluation of new ADAM-17 inhibitors containing an arylsulfonamidic scaffold. Among the new potential inhibitors, two very promising compounds 17 and 18 were discovered, with a nanomolar activity for ADAM-17 isolated enzyme. These compounds proved to be also the most potent in inhibiting soluble ALCAM release in cancer cells, showing a nanomolar activity on A2774 and SKOV3 cell lines.
Nuti, Elisa; Casalini, F; AVRAMOVA S., I; Santamaria, S; Fabbi, M; Ferrini, S; Marinelli, L; LA PIETRA, V; Limongelli, V; Novellino, E; Cercignani, Giovanni; Orlandini, Elisabetta; Nencetti, Susanna; Rossello, Armando
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/205057
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