The metalloproteinase ADAM8 is upregulated in several cancers but has a dispensable function under physiological conditions. In tumor cells, ADAM8 is involved in invasion, migration and angiogenesis. The use of bivalent inhibitors could impair migration and invasion, through the double binding to a homodimeric form of ADAM8 located on the cell surface of tumor cells. Herein we report the rational design and synthesis of the first dimeric ADAM8 inhibitors selective over ADAM10 and MMPs. Bivalent derivatives have been obtained by dimerizing the structure of a previously described ADAM17 inhibitor, JG26. In particular, derivative 2 showed to inhibit ADAM8 proteolytic activity in vitro and in cell-based assays, at nanomolar concentration. Moreover, it was more effective than the parent monomeric compound in blocking invasiveness in breast cancer MDA-MB-231 cell line, thus supporting our hypothesis about the importance of inhibiting the active homodimer of ADAM8.

Discovery of Dimeric Arylsulfonamides as Potent ADAM8 Inhibitors

Cuffaro, Doretta
Primo
;
Camodeca, Caterina;Tuccinardi, Tiziano;Ciccone, Lidia;Nuti, Elisa
Penultimo
;
Rossello, Armando
2021-01-01

Abstract

The metalloproteinase ADAM8 is upregulated in several cancers but has a dispensable function under physiological conditions. In tumor cells, ADAM8 is involved in invasion, migration and angiogenesis. The use of bivalent inhibitors could impair migration and invasion, through the double binding to a homodimeric form of ADAM8 located on the cell surface of tumor cells. Herein we report the rational design and synthesis of the first dimeric ADAM8 inhibitors selective over ADAM10 and MMPs. Bivalent derivatives have been obtained by dimerizing the structure of a previously described ADAM17 inhibitor, JG26. In particular, derivative 2 showed to inhibit ADAM8 proteolytic activity in vitro and in cell-based assays, at nanomolar concentration. Moreover, it was more effective than the parent monomeric compound in blocking invasiveness in breast cancer MDA-MB-231 cell line, thus supporting our hypothesis about the importance of inhibiting the active homodimer of ADAM8.
2021
Cuffaro, Doretta; Camodeca, Caterina; Tuccinardi, Tiziano; Ciccone, Lidia; Bartsch, Jörg W.; Kellermann, Tanja; Cook, Lena; Nuti, Elisa; Rossello, Armando
File in questo prodotto:
File Dimensione Formato  
Cuffaro 2021.pdf

accesso aperto

Descrizione: Articolo principale
Tipologia: Versione finale editoriale
Licenza: Creative commons
Dimensione 4.08 MB
Formato Adobe PDF
4.08 MB 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/11568/1110404
Citazioni
  • ???jsp.display-item.citation.pmc??? 2
  • Scopus 3
  • ???jsp.display-item.citation.isi??? 2
social impact