6-diazo-5-oxonorleucine

6-diazo-5-oxonorleucine (DON) is a non-proteinogenic amino acid and a classic, broadly active glutamine antagonist originally isolated from *Streptomyces* species. It acts as an irreversible, covalent inhibitor of multiple glutamine-utilizing enzymes, including glutaminase (GLS/GLS2), CTP synthase (CTPS1), glutamine--fructose-6-phosphate aminotransferase (GFPT1), and several enzymes involved in purine and pyrimidine de novo synthesis. Although historically investigated as an anticancer agent in the 1950s through the 1980s, its clinical development for oncology was abandoned due to severe, dose-limiting gastrointestinal toxicities. More recently, DON has been investigated as an adjunctive therapy for cerebral malaria in Phase I/II clinical trials, and its scaffold has served as the basis for tumor-targeted prodrugs (such as DRP-104) designed to minimize systemic toxicity.

Other names

(S)-2-amino-6-diazo-5-oxohexanoic acid6-diazo-5-oxo-L-norleucineDONDiazooxonorleucineL-6-Diazo-5-oxonorleucineL6-Diazo-5-oxonorleucineL 6-Diazo-5-oxonorleucineL-DONdiazo-oxo-norleucine