Selective Arylsulfonamide Inhibitors of ADAM-17: Hit Optimization and Activity in Ovarian Cancer Cell Models

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• 作者：Elisa Nuti ; Francesca Casalini ; Salvatore Santamaria ; Marina Fabbi ; Grazia Carbotti ; Silvano Ferrini ; Luciana Marinelli ; Valeria La Pietra ; Ettore Novellino ; Caterina Camodeca ; Elisabetta Orlandini ; Susanna Nencetti ; Armando Rossello
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：October 24, 2013
• 年：2013
• 卷：56
• 期：20
• 页码：8089-8103
• 全文大小：535K
• 年卷期：v.56,no.20(October 24, 2013)
• ISSN：1520-4804

文摘

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.