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.