Glutamine inhibitors are compounds that interfere with cellular processes involving glutamine, an abundant amino acid. These inhibitors specifically disrupt how cells acquire or use glutamine, limiting its availability or preventing its conversion into other necessary molecules. This disruption impacts various cellular functions, especially in cells with high glutamine demand. Their development explores new ways to influence cell behavior by manipulating metabolic pathways.
The Role of Glutamine
Glutamine is the most abundant free amino acid in human blood, playing a multifaceted role in cellular health. It provides carbon and nitrogen for various biosynthetic processes, including nucleotides for DNA and RNA, fatty acids, and other non-essential amino acids. Glutamine is also a significant energy source for cells, particularly through glutaminolysis, which feeds into the tricarboxylic acid (TCA) cycle for energy production.
Rapidly dividing cells, such as tumor cells, show a high dependence on glutamine to fuel their growth and proliferation. This increased demand is often called “glutamine addiction.” Cancer cells reprogram their metabolism for a steady glutamine supply, supporting their high metabolic activity and continuous division. Glutamine also helps maintain cellular redox balance by supporting glutathione production, an antioxidant that protects these cells from oxidative stress.
Immune cells also rely heavily on glutamine for their activation, proliferation, and function. This amino acid supports lymphocyte proliferation, macrophage phagocytic activity, and neutrophil bacterial killing. Glutamine’s central role in both normal physiological processes and disease progression makes its metabolic pathways an attractive therapeutic target.
Mechanisms of Glutamine Inhibitors
Glutamine inhibitors disrupt specific steps in glutamine metabolism. One primary target is the enzyme glutaminase (GLS), which converts glutamine to glutamate. Humans have two main forms, GLS1 and GLS2, with GLS1 having two splice variants. Inhibiting these enzymes reduces glutamate availability, a precursor for many essential biosynthetic pathways.
Glutaminase inhibitors include glutamine antimetabolites like L-DON, azaserine, and acivicin. These are competitive inhibitors that bind irreversibly to the active site of glutaminases and other glutamine-utilizing enzymes. They mimic glutamine, blocking its normal processing. However, their broad inhibition can lead to significant systemic toxicity.
A more selective approach uses allosteric glutaminase inhibitors, which bind to a site on the enzyme distinct from the active site, altering its activity. Examples include BPTES and CB-839 (Telaglenastat). BPTES inhibits GLS1 by stabilizing an inactive tetrameric conformation of the enzyme, while CB-839 is a potent, orally bioavailable GLS1 inhibitor. Compound 968 shows selectivity for GLS2 over GLS1.
Beyond enzyme inhibition, some glutamine inhibitors target transporters responsible for glutamine uptake into cells. Glutamine enters cells via specific transporters. Inhibitors like V-9302 and JPH203 interfere with these, limiting extracellular glutamine influx. By disrupting uptake or metabolic conversion, these inhibitors aim to starve cells of fuel and building blocks needed for growth and survival.
Therapeutic Applications
Glutamine inhibitors are primarily explored for cancer therapy, as many tumor types highly depend on glutamine for growth and survival. Targeting glutamine metabolism can disrupt energy production, the synthesis of nucleotides, amino acids, and lipids, and the maintenance of redox balance within cancer cells. For example, glutaminase inhibitors like CB-839 have shown promise in preclinical studies and early-phase clinical trials for various cancers, including breast cancer, renal cell carcinoma, and hematological malignancies.
Inhibiting glutamine metabolism in cancer is often combined with other therapies to enhance effectiveness. Cancer cells can compensate for glutamine deprivation by activating alternative metabolic pathways, such as glycolysis or fatty acid oxidation. Combining glutamine inhibitors with traditional chemotherapies or immune checkpoint inhibitors is an active research area to overcome resistance and improve patient outcomes. For instance, DRP-104 is being studied with durvalumab for fibrolamellar tumors, aiming to starve tumor cells and enhance the immune response.
Beyond cancer, glutamine inhibitors are investigated for other therapeutic areas. In autoimmune diseases, CD4+ T cells rely on glutamine for differentiation and function. Targeting glutamine metabolism in these immune cells, including transporters and GLS1, may offer a selective approach to modulate immune responses. Research also suggests that inhibiting glutamine metabolism, particularly through glutaminase inhibitors, could block the replication of certain viruses, including coronaviruses like SARS-CoV-2, by disrupting host cell metabolism.