title: Selective arylsulfonamide inhibitors of ADAM-17: hit optimization and activity in ovarian cancer cell models.
abstract: Activated leukocyte cell adhesion molecule (ALCAM) is expressed at the surface of epithelial ovarian cancer (EOC) cells and is released in a soluble 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 addition, ADAM-17 plays a key role in EGFR signaling 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 previously identified inhibitor 1. A new series of secondary sulfonamido-based hydroxamates was designed and synthesized. The biological activity of the newly synthesized compounds was tested in vitro on isolated enzymes and human EOC cell lines. The optimization process led to compound 21, which showed an IC50 of 1.9 nM on ADAM-17 with greatly increased selectivity. This compound maintained good inhibitory properties on sALCAM shedding in several in vitro assays.
authors.affiliation: Dipartimento di Farmacia, Università di Pisa , Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Nuti
authors.forename: Francesca
authors.initials: F
authors.lastname: Casalini
authors.forename: Salvatore
authors.initials: S
authors.lastname: Santamaria
authors.forename: Marina
authors.initials: M
authors.lastname: Fabbi
authors.forename: Grazia
authors.initials: G
authors.lastname: Carbotti
authors.forename: Silvano
authors.initials: S
authors.lastname: Ferrini
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Valeria
authors.initials: V
authors.lastname: La Pietra
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Caterina
authors.initials: C
authors.lastname: Camodeca
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Orlandini
authors.forename: Susanna
authors.initials: S
authors.lastname: Nencetti
authors.forename: Armando
authors.initials: A
authors.lastname: Rossello
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000072198:ADAM17 Protein; D020410:Activated-Leukocyte Cell Adhesion Molecule / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D020410:Activated-Leukocyte Cell Adhesion Molecule; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D013449:Sulfonamides; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human