Therapeutics: Thymidylate synthetase (TYMS)

In vitro and mouse studies identified an oral phosphoramidate-based prodrug of the TYMS inhibitor floxuridine that could help treat hepatocellular carcinoma (HCC). Chemical synthesis of benzylamine phosphoramidate analogs of floxuridine followed by testing in a human HCC cell line yielded a compound that inhibited growth with an IC50 of 250 μM. In a xenograft mouse model of HCC, the compound decreased tumor growth compared with vehicle, without observable weight loss, organ damage or other toxic side effects. Next steps could include testing of the compound in additional models of liver cancer.

The generic floxuridine, delivered IV into the hepatic artery, is marketed to treat liver cancer and liver metastases of colorectal cancer...