New Heparanase-Inhibiting Triazolo-Thiadiazoles Attenuate Primary Tumor Growth and Metastasis

Abstract

Compelling evidence ties heparanase, an endoglycosidase that cleaves heparan sulfate side (HS) chains of proteoglycans, with all steps of tumor development, including tumor initiation, angiogenesis, growth, metastasis, and chemoresistance. Moreover, heparanase levels correlate with shorter postoperative survival of cancer patients, encouraging the development of heparanase inhibitors as anti-cancer drugs. Heparanase-inhibiting heparin/heparan sulfate-mimicking compounds and neutralizing antibodies are highly effective in animal models of cancer progression, yet none of the compounds reached the stage of approval for clinical use. The present study focused on newly synthesized triazolo–thiadiazoles, of which compound 4-iodo-2-(3-(p-tolyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)phenol (4-MMI) was identified as a potent inhibitor of heparanase enzymatic activity, cell invasion, experimental metastasis, and tumor growth in mouse models. To the best of our knowledge, this is the first report showing a marked decrease in primary tumor growth in mice treated with small molecules that inhibit heparanase enzymatic activity. This result encourages the optimization of 4-MMI for preclinical and clinical studies primarily in cancer but also other indications (i.e., colitis, pancreatitis, diabetic nephropathy, tissue fibrosis) involving heparanase, including viral infection and COVID-19.

Spectroscopic characterization and assessment of microbiological potential of 1,3,4-thiadiazole derivative showing ESIPT dual fluorescence enhanced by aggregation effects

“…Recently, searching for new agents with antifungal activity has become more important because of the increase in frequency of severe fungal infections and the expansion of fungal resistance to drugs 4 . Selected derivatives from the group of 1,3,4-thiadiazoles prove potentially beneficial effects in the treatment and prevention of said diseases 5,6 , and some of them have already found clinical applications 7,8 . Their unusual spectroscopic and crystallographic properties dictate a large spectrum of their additional applications; they can be used as laser pigments 9 , ligands complexing rare earth metal ions 10 , molecular probes 11 , as well as UV stabilizers 12 .…”

The Role and Therapeutic Value of Syndecan-1 in Cancer Metastasis and Drug Resistance

“…Lately, a newly synthesized triazolo–thiadiazoles (4-MMI) has been shown to successfully inhibit enzymatic heparanase activity and heparanase-mediated VEGF gene expression, restraining the ability of carcinoma cells to extravasate through the subendothelial basement membrane. It’s shown that 4-MMI yield a nearly fourfold inhibition of 4T1 breast carcinoma metastasis, comparable to the effect exerted by roneparstat ( Barash et al, 2021 ).…”

Heparin–Superparamagnetic Iron Oxide Nanoparticles for Theranostic Applications

“…We next investigated the ability of our LMWH@SPION preparations to abrogate heparanase of its native oligosaccharide substrates, using a colorimetric assay that detects the cleavage of the synthetic HS pentasaccharide fondaparinux [ 44 , 45 ]. The dose-dependent inhibition of the heparanase-mediated fondaparinux cleavage was exerted by both SPION3 (estimated IC50 = ~200 ng/mL) and SPION4 (estimated IC50 = ~70 ng/mL) ( Figure 7 ).…”

“…Colorimetric (Arixtra) assay: The assay was carried out in a 96-well plate in which the formation of the disaccharide product upon the cleavage of fondaparinux (Arixtra, GlaxoSmithKline, Brentford, UK) was estimated using WST-1 tetrazolium salt, as described earlier [ 45 ].…”