The latest research on 6-DIAZO-5-OXO-L-NORLEUCINE

6-DIAZO-5-OXO-L-NORLEUCINE is a glutamine antagonist, which was originally isolated from Streptomyces in Peruvian soil samples. This diazo compound is biosynthesized from lysine by three enzymes in bacteria. It is one of the most famous non-proteinogenic amino acids, and it is considered to be the most effective chemotherapy product in the future in different clinical tests. In 2019, DON combined with calorie-restricted ketogenic diet was proved to kill tumor cells, reverse disease symptoms and improve the overall survival rate of advanced experimental glioblastoma in mice.

What is glutamine antagonist?

Scientists have always believed that the metabolic pattern of cancer is different from that of healthy cells, and the concept of targeting cancer metabolism is constantly growing and developing based on this. The scientific community believes that one difference between normal cells and cancer cells is that normal cells can perceive nutrient deficiency and stop proliferation, while cancer cells experience abnormal growth due to the drive of oncogenes, and they continue to rely on nutrient supply. From this perspective, nutrient deprivation may trigger cell death in cancer cells. We know that cellular metabolism can be divided into several categories: glucose, amino acids, fatty acids, nucleotides, and mitochondrial metabolism, and glutamine can be used as a nitrogen donor for the synthesis of asparagine, hexosamine, purine, and pyrimidine. If its synthesis process can be inhibited, it will exert anti-cancer activity. And it can avoid the side effects of inhibiting glutamine metabolism in healthy cells. DRP-104 (also known as sirpiglenastat) developed by the Dracen Pharmaceuticals team is a well-known glutamine antagonist that can simultaneously target multiple metabolic pathways involving glutamine. After being cleaved by enzymes enriched in tumors, it produces activity and can directly kill tumors locally.

What is the latest research theory on glutamine?

Glutamine addiction is an important part of tumor metabolic reprogramming and a significant feature of cancer cell growth. Therefore, the discovery of antagonists that can widely inhibit glutamine metabolism has become crucial and a hot topic in current anti-cancer drug development. Among them, the natural compound DON is currently the most widely studied glutamine antagonist, with the highest advancement to phase II clinical research. However, clinical trials have revealed its narrow treatment window and significant gastrointestinal side effects. This is mainly because normal gastrointestinal cells also rely on glutamine, leading to a large accumulation of DON in gastrointestinal tissues, interfering with normal glutamine metabolism and causing harm to healthy tissues.

The toxicity of (S)-2-Amino-6-diazo-5-oxocaproic acid originates from its pharmacological mechanism, and conventional structural modifications cannot achieve attenuation while maintaining its efficacy. Only by introducing targeting groups with specific recognition functions, designing and synthesizing tumor targeted DON prodrugs, and selectively delivering the drug to the lesion site, can the toxic effects on normal cells, tissues, and organs be reduced, thereby improving its therapeutic window. How to utilize the differences in the microenvironment between tumors and normal cells to achieve targeted drug release through site-specific activation is the key and difficult point for the further development of H-L-Don-OH as a glutamine metabolism antagonist in clinical practice.

How to achieve the effect of targeted specific activation?

Phototriggered prodrugs have shown great potential in the field of cancer treatment due to their non-invasive and controllable nature. Near infrared light has also become the preferred light source for phototherapy due to its low energy, minimal tissue damage, and high tissue permeability. The optimal compound structure designed and synthesized in this study is DON-TK-BM3, which combines isopropyl protected L-DON with cyanine dye via ROS responsive thioketal chain (TK). Under near-infrared light irradiation, the cyanine dye generates singlet oxygen, causing the TK chain to break and releasing H-6-Diazo-5-oxo-Nle-OH and cyanine probes. This design not only achieves precise targeted accumulation of DON in tumor tissues and optimizes the drug release mechanism ("how to release"), but also changes the fluorescence spectrum through structural changes before and after drug release, providing accurate information on release time ("when to release"). In vivo activity studies further demonstrate that DON-TK-BM3 not only implements a photodynamic therapy strategy, inhibits the tricarboxylic acid cycle (TCA) of tumor cells, reverses the immunosuppressive microenvironment of tumors, but also significantly enhances anti-tumor effects while significantly reducing drug side effects. These research results not only demonstrate the broad potential of this prodrug technology in clinical applications, but also provide new strategic directions for drug development targeting cancer metabolic targets.

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