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

SIMPLE SUMMARY: Heparanase is an endoglycosidase that plays a critical role in tumor progression and metastasis. The expression of heparanase in the tumor microenvironment is positively correlated with the aggressiveness of the tumor and is associated with poor prognosis. In this study, we have demonstrated that a new triazole–thiadiazole-bearing small molecule showed good heparanase inhibition along with attenuation of tumor growth and metastasis. To the best of our knowledge, this is the first report showing a marked decrease in primary tumor growth in mice treated with a small molecule that inhibits heparanase enzymatic activity. Given these encouraging results, studies are underway to better elucidate the mode of action and clinical significance of triazolo–thiadiazoles. 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.