6-diazo-5-oxo-L-norleucine (DON)

6-diazo-5-oxo-L-norleucine (DON) is a non-proteinogenic amino acid and a potent glutamine antagonist originally isolated from Streptomyces bacteria. It is not a biological target itself but rather a small molecule inhibitor that targets a wide array of glutamine-utilizing enzymes, including glutaminase (GLS), CTP synthase, and various amidotransferases involved in purine and pyrimidine biosynthesis. By mimicking the structure of L-glutamine, DON enters the active site of these enzymes and forms a covalent bond, leading to irreversible inhibition of critical metabolic pathways required for cell proliferation. In the context of oncology, DON has demonstrated significant anti-tumor activity by depleting the nitrogen sources necessary for DNA synthesis and disrupting the metabolic reprogramming common in cancer cells. However, its clinical utility as a standalone agent has been historically limited by severe systemic toxicities, particularly affecting the gastrointestinal tract, where glutamine metabolism is essential for mucosal integrity. Modern therapeutic strategies involve the development of DON prodrugs, such as DRP-104 and JHU-083, which are designed to release the active DON molecule preferentially within the tumor microenvironment to enhance efficacy while minimizing peripheral side effects (Source: National Cancer Institute, PubMed PMID: 31740587).

Other names

DONL-DON6-Diazo-5-oxo-norleucineNSC 7365

6-diazo-5-oxo-L-norleucine acts as a prodrug or active inhibitor that covalently binds to the catalytic site of glutamine-utilizing enzymes, specifically targeting the conserved cysteine or serine residues in the glutamine-binding domain to irreversibly inhibit their activity (Source: PubChem, PubMed PMID: 28842570).