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New Heparanase-Inhibiting Triazolo-Thiadiazoles Attenuate Primary Tumor Growth and Metastasis
| Content Provider | MDPI |
|---|---|
| Author | Barash, Uri Rangappa, Shobith Mohan, Chakrabhavi Vishwanath, Divakar Boyango, Ilanit Basappa, Basappa Vlodavsky, Israel Rangappa, Kanchugarakoppal |
| Copyright Year | 2021 |
| Description | 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. |
| Starting Page | 2959 |
| e-ISSN | 20726694 |
| DOI | 10.3390/cancers13122959 |
| Journal | Cancers |
| Issue Number | 12 |
| Volume Number | 13 |
| Language | English |
| Publisher | MDPI |
| Publisher Date | 2021-06-13 |
| Access Restriction | Open |
| Subject Keyword | Cancers Medicinal Chemistry Triazolo–thiadiazoles Small Molecules Heparanase-inhibiting Compounds Primary Tumor Growth Cell Invasion Metastasis |
| Content Type | Text |
| Resource Type | Article |
