Selective Arylsulfonamide Inhibitors of ADAM-17: Hit Optimization and Activity in Ovarian Cancer Cell Models
Copyright policy )Selective Arylsulfonamide Inhibitors of ADAM-17: Hit Optimization and Activity in Ovarian Cancer Cell Models
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.
- University of Pisa Italy
- University Federico II of Naples Italy
- Ospedale San Martino Italy
Models, Molecular, Ovarian Neoplasms, Sulfonamides, Dose-Response Relationship, Drug, Molecular Structure, Cell Survival, ADAM17 Protein, Crystallography, X-Ray, Hydroxamic Acids, Protein Structure, Tertiary, ADAM Proteins, Models, Chemical, Cell Movement, Activated-Leukocyte Cell Adhesion Molecule, Cell Line, Tumor, Humans, Female, Enzyme Inhibitors, Protein Binding
Models, Molecular, Ovarian Neoplasms, Sulfonamides, Dose-Response Relationship, Drug, Molecular Structure, Cell Survival, ADAM17 Protein, Crystallography, X-Ray, Hydroxamic Acids, Protein Structure, Tertiary, ADAM Proteins, Models, Chemical, Cell Movement, Activated-Leukocyte Cell Adhesion Molecule, Cell Line, Tumor, Humans, Female, Enzyme Inhibitors, Protein Binding
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).24 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Average impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10%
Citations provided by BIP!Popularity provided by BIP!