Renaissance of 6-Diazo-5-oxo-ʟ-norleucine (DON): Prodrug Strategy as a Promising Tool Leading to Potential Anticancer Drug

The natural compound 6-diazo-5-oxo-ʟ-norleucine (DON) has shown promising anticancer activity in several preclinical and early clinical studies, but its further development has been hampered by adverse toxicity, mainly in the gastrointestinal tract. This review discusses the renaissance of DON through prodrug strategies. Using rational strategies, we have developed hundreds of tumor- and brain-targeted prodrugs with improved pharmaco­kinetic and pharmacodynamic properties and without severe toxicity. The most promising prodrug, sirpiglenastat, entered clinical trials in 2020 under the leadership of Dracen Pharmaceuticals and is currently being tested in combination with durvalumab in patients with fibrolamellar hepatocellular carcinoma.