Potent Arylsulfonamide Inhibitors of Tumor Necrosis Factor-α Converting Enzyme Able to Reduce Activated Leukocyte Cell Adhesion Molecule Shedding in Cancer Cell Models

Abstract

Activated leukocyte cell adhesion molecule (ALCAM) plays a relevant role in tumor biology and progression. Our previous studies showed that ALCAM is expressed at the surface of epithelial ovarian cancer (EOC) cells and is released in a soluble form by ADAM-17-mediated shedding. This process is relevant to EOC cell motility and invasiveness, which is reduced by nonspecific inhibitors of ADAM-17. For this reason, ADAM-17 may represent a new useful target in anticancer therapy. Herein, we report the synthesis and biological evaluation of new ADAM-17 inhibitors containing an arylsulfonamidic scaffold. Among the new potential inhibitors, two very promising compounds 17 and 18 were discovered, with a nanomolar activity for ADAM-17 isolated enzyme. These compounds proved to be also the most potent in inhibiting soluble ALCAM release in cancer cells, showing a nanomolar activity on A2774 and SKOV3 cell lines.

Synthesis, experimental evaluation and molecular modelling of hydroxamate derivatives as zinc metalloproteinase inhibitors

“…The compounds ARP101, EN178, LM2 and FC19 were synthesised as previously reported [21][22][23][24]. Compound EN204 was prepared as described in Scheme 1.…”

Activated leukocyte cell adhesion molecule soluble form: a potential biomarker of epithelial ovarian cancer is increased in type II tumors

“…Therefore ADAM17/TACE has been regarded as a potential target in ovarian tumors, as well as in other EGF‐dependent neoplasias 15. In this context, arylsulfonamide inhibitors of ADAM17/TACE were able to reduce ALCAM shedding in ovarian cancer cells16 and limit in vitro cell migration 10…”

How to exploit stress-related immunity against Hodgkin’s lymphoma

“… 50 - 53 First, the expression of membrane-bound NKG2DLs by cancer cells might be stimulated by drugs such as ATRA and VPA or, as recently reported, by proteasome inhibitors, 5 , 6 , 15 , 54 - 56 all of which have already been approved for the treatment of hematological malignancies. Second, ERp5, ADAM10 and ADAM17 may represent targets for selective inhibitors of their enzymatic activity 44 - 49 . Recent preclinical data based on the use of ADAM17 inhibitors for the treatmen of solid neoplasms appear to support this notion 57 .…”

“…Blocking ERp5 would be possible with antagonistic peptides that mimic the α3 domain of MICA and hence impede the interaction of the enzyme with its substrate 44 - 46 . Conversely, pharmacological inhibitors of ADAM10 and ADAM17 with some degree of selectivity have already been developed 47 - 49 …”