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

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.
Nuti, Elisa; Casalini, Francesca; Santamaria, Salvatore; Fabbi, Marina; Carbotti, Grazia; Ferrini, Silvano; Marinelli, Luciana; La Pietra, Valeria; Novellino, Ettore; Camodeca, Caterina; Orlandini, Elisabetta; Nencetti, Susanna; Rossello, Armando
File in questo prodotto:
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.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/266135
Citazioni
  • ???jsp.display-item.citation.pmc??? 7
  • Scopus 19
  • ???jsp.display-item.citation.isi??? 18
social impact