Activated Leukocyte Cell Adhesion Mol. (ALCAM) is expressed at the surface of epithelial ovarian cancer (EOC) cells and is released in a sol. form (sALCAM) by ADAM-17-mediated shedding. This process is relevant to EOC cell motility and invasiveness, which is reduced by inhibitors of ADAM-17. In addn., ADAM-17 plays a key role in EGFR signalling and thus may represent a useful target in anticancer therapy. Herein we report our hit optimization effort to identify potent and selective ADAM-17 inhibitors, starting with previous mol. 1. A new series of secondary sulfonamido-based hydroxamates was designed and synthesized. The biol. activity of the newly synthesized compds. was tested in vitro on isolated enzymes and human EOC cell lines. The optimization process led to compd. 21, which showed an IC50 of 1.9 nM on ADAM-17 with greatly increased selectivity. This compd. maintained good inhibitory properties on sALCAM shedding in several in vitro assays.
Selective Arylsulfonamide Inhibitors of ADAM-17: Hit Optimization and Activity in Ovarian Cancer Cell Models
NUTI, ELISA;ORLANDINI, ELISABETTA;NENCETTI, SUSANNA;ROSSELLO, ARMANDO
2013-01-01
Abstract
Activated Leukocyte Cell Adhesion Mol. (ALCAM) is expressed at the surface of epithelial ovarian cancer (EOC) cells and is released in a sol. form (sALCAM) by ADAM-17-mediated shedding. This process is relevant to EOC cell motility and invasiveness, which is reduced by inhibitors of ADAM-17. In addn., ADAM-17 plays a key role in EGFR signalling and thus may represent a useful target in anticancer therapy. Herein we report our hit optimization effort to identify potent and selective ADAM-17 inhibitors, starting with previous mol. 1. A new series of secondary sulfonamido-based hydroxamates was designed and synthesized. The biol. activity of the newly synthesized compds. was tested in vitro on isolated enzymes and human EOC cell lines. The optimization process led to compd. 21, which showed an IC50 of 1.9 nM on ADAM-17 with greatly increased selectivity. This compd. maintained good inhibitory properties on sALCAM shedding in several in vitro assays.File | Dimensione | Formato | |
---|---|---|---|
jm4011753.pdf
non disponibili
Tipologia:
Versione finale editoriale
Licenza:
Importato da Ugov Ricerca - Accesso privato/ristretto
Dimensione
1.68 MB
Formato
Adobe PDF
|
1.68 MB | Adobe PDF | Visualizza/Apri Richiedi una copia |
jm4011753_si_001.pdf
non disponibili
Tipologia:
Altro materiale allegato
Licenza:
Importato da Ugov Ricerca - Accesso privato/ristretto
Dimensione
127.34 kB
Formato
Adobe PDF
|
127.34 kB | Adobe PDF | Visualizza/Apri Richiedi una copia |
Accepted manuscript.pdf
accesso aperto
Tipologia:
Documento in Post-print
Licenza:
Tutti i diritti riservati (All rights reserved)
Dimensione
794.61 kB
Formato
Adobe PDF
|
794.61 kB | Adobe PDF | Visualizza/Apri |
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.