Glutamine antagonist examples. 2013; Nissen-Meyer and Chaudhry 2013).

Glutamine antagonist examples Tumors often achieve this by pumping increasing levels of the amino acid glutamine into their cells, primarily through a pump called SLC1A5. (C–E) Effect of low-affinity, fast-equilibrating AMPA receptor antagonist γ-DGG. 2013; Nissen-Meyer and Chaudhry 2013). 6-Diazo-5-oxo-l-norleucine (DON), a glutamine antagonist, previously showed promising antitumor effects (). The PDAC TME consists of a dense fibrous stroma (desmoplasia) and heterogeneous cellular A compound developed by Johns Hopkins researchers that blocks glutamine metabolism can slow tumor growth, alter the tumor microenvironment and promote the production of durable and highly active Glutamine metabolism inhibitors include glutamine antimetabolites and their prodrug forms and allosteric glutaminase inhibitors. 33–35 Recently, Glutamine antagonist promotes allograft acceptance in a mouse model of skin transplantation BALB/c to C57BL/6 skin graft survival, For example, Th1 and Th17 cells have been found to depend on glutaminolysis and regulatory T This was the only example of a drug that could be given “late” in the disease process, after symptom onset, a common clinical scenario in both pediatric and adult CM. Each subunit is individually rainbow colored. While Gln is non-essential for non-malignant prostate epithelial cells, PCa cells become highly dependent on an exogenous source of Gln. Then, glutamine transporters provide cells with this special nutrient. Our findings were consistent with multiple studies demonstrating that glutamine antagonists exhibit promise as neuroprotective agents. Cells were treated The presently disclosed subject matter relates to methods, uses, and pharmaceutical compositions comprising at least one glutamine antagonist, or a prodrug or analog thereof, for the treatment of cognitive deficits, such as those associated with neurological or neurodegenerative disorders, psychiatric or mood disorders, and HIV-associated neurocognitive disorders (HAND)). JHU395 delivers 6-diazo-5-oxo-L-norleucine (DON) to malignant peripheral nerve sheath tumor Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25. We performed cell growth, cell cycle, A compound that blocks glutamine metabolism can slow tumor growth, alter the tumor microenvironment and promote the production of durable and highly active anti-tumor T This chapter deals primarily with compounds whose biological activity may be ascribed to interference with functions of glutamine. Glutamine is an amino acid found in both animal and plant protein; it is the most abundant amino acid in the human body - it is non-essential, you make it yourself in your muscles from where it supplies other organs; 25% is found in your brain. The biochemical pharmacology of this agent is unique among antimetabolites and offers several interesting possibilities for combination therapy with agents whose activity can be potentiated by acivicin, with agents which can interfere with cellular For example, the glutamine transporter inhibitor V-9302 selectively inhibits glutamine uptake by tumor, but not CD8 + T, cells. We demonstrate that glutamine blockade in tumor-bearing mice suppresses o The metabolic characteristics of tumors present considerable hurdles to immune cell function and cancer immunotherapy. However, severe dose-limiting gastrointestinal toxicities associated with DON have led to the termination of studies for its clinical development . Using the glutamine-antagonist prodrug JHU083, we report potent tumor growth inhibition in urologic tumors by JHU083-reprogrammed tumor-associated macrophages (TAMs) and tumor-infiltrating monocytes. Here, using patient-derived xenograft models and antigenic orthotopic lung cancer models, we show that the novel glutamine antagonist DRP-104 impairs the growth of KEAP1 mutant tumors. DRP-104 is preferentially distributed in tumors where it is bio-transformed and activated to the active moiety DON. Skip to For example, de novo pyrimidine synthesis was identified as a metabolic vulnerability of triple The interest around glutamine metabolism lies in its physio-pathological role; glutamine is considered a conditionally essential amino acid because highly proliferative cells have an increased request of glutamine that cannot be satisfied only by endogenous synthesis. 5-HTP is a synthetic form of tryptophan, which is found in turkey. A key feature associated with this poor prognosis is the complex tumor microenvironment (TME) in which these tumors develop 3. 2 Glutamatergic hypothesis of schizophrenia. Some consideration is also given to molecules that To harness the potent anti-tumor effects of 6-Diazo-5-oxo-L-norleucine (DON) which targets glutamine utilizing enzymes and to mitigate known significant toxicities, we here use a novel Benefitting from the marvelous potential of reactive oxygen species (ROS)-mediated dynamic therapies in tumor immunocombination therapy due to their immunogenic cell death For example, pyruvate can be generated from malate, concomitant with the production of NADPH via malic enzyme 1 (ME1) prodrugs of the glutamine antagonist DON together with optimized delivery strategies and dosages may show promising outcomes in patients with glutamine-addicted tumors in clinical trials in the future. In summary, we report the discovery of a first-in-class prodrug that exhibits divergent metabolism in target versus toxicity tissue sites, leading to a well-tolerated glutamine Here, using immunodeficient and immunocompetent orthotopic murine cancer models, we demonstrate that DRP-104, a broad-acting glutamine Several cancers have been described as “glutamine-addicted” because of their exceptional metabolic demands. Here the authors show that glutamine metabolism is sufficient to restore mTORC1 activity during prolonged amino acid starvation in an autophagy-dependent manner. , 2011). As detailed in several chapters throughout this volume, the glutamate–glutamine cycle does not operate isolated from other biological processes—it is affected by numerous metabolic and signaling pathways within and outside the CNS , as Recent examples exist of successful translation of discovered cancer cell metabolic derangements into FDA-approved metabolic inhibitors. In the United States, approximately 2 million new cancer cases and 0. Therefore, glutamine antagonism can inhibit lymphocyte proliferation (Wang et al. They predominantly work at the GABA receptor. [Google Scholar] Pochini L. e. PDF | Background Metabolism reprogramming is a common feature in cancer, and it is critical to facilitate cancer cell growth. Pathologically, there is degeneration and loss of the motor neurons in the spinal Xie et al. The inhibition is also completely relieved by cytidine in noncompetitive manner, but not by guanosine or uridine, indicating that the principal damage to the cellular economy Glutamine metabolism plays an important role in the activation of macrophages, and there are inherent differences in the dependence of different macrophage subsets on glutamine. Unraveling the orchestration of glutamine metabolism may provide a novel viewpoint on GBM therapy. In the study, Ronai and his team set out to identify drug(s) that can inhibit glutamine uptake. Glutamate is synthesized from the nonessential amino acid glutamine, For example, mGlu 1 and mGlu 5 are predominantly in the amygdala, hippocampus and thalamus, whereas mGlu 3 is located primarily on glia Ketamine acts as a noncompetitive antagonist of NMDA receptors, thus inhibiting downstream neuronal activation pathways The glutamine antagonist DRP-104 blocks purine synthesis and combines with checkpoint inhibitors to promote antitumor immunity in KEAP1/NRF2-mutant lung cancers. The researchers’ conclusions are similar to many others – ketamine could be a safe and effective way to treat depression. Examples include caspase-3, caspase-6, and caspase-7. Main. The amino acid glutamine is consumed by effector T cells and glutamine-addicted triple-negative breast cancer (TNBC) cells, suggesting that a metabolic competition for glutamine may exist within the tumor microenvironment, potentially The glutamine transporting protein is found to be elevated in a number of cancers, including colon cancer, breast cancer, and lung cancer. We find that DRP-104 suppresses KEAP1 mutant tumor growth by inhibiting glutamine-dependent nucleotide synthesis and promoting anti-tumor CD4 and CD8 T cell Glutamine (Gln) is a non-essential amino acid that is involved in the development and progression of several malignancies, including prostate cancer (PCa). Besides, it also participates in maintaining of a normal blood glucose level and the proper pH range. However, efforts to drug this process are confounded by the intrinsic metabolic heterogeneity and flexibility of tumors, as well as the risk of adverse effects on the anticancer immune response. 19 sNF96. Recent research has yielded important Possible paradigms of defining the critical limiting metabolite. 2024 Mar 29;10(13):eado7808. 3 The Glutamate–Glutamine Cycle is Part of an Extensive Cellular, Molecular, and Metabolic Homeostatic Network. 0 mg/mL) to 900 μL Corn oil, and mix evenly. Glutamine metabolism, synthesis, and regulation by oncogenes. Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer Ray Pillai1,2,3†, Sarah E. Excitatory amino acid receptor antagonist; Excitatory amino acid reuptake inhibitor; References External links. Here, we disclose the critical Rapidly proliferating tumor and immune cells need metabolic programs that support energy and biomass production. Despite the promise of glutamine deprivation strategies, (JHU083) of the glutamine antagonist DON, The glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON, 14), which is known to inhibit. Histamine Antagonists Accession Number DBCAT000664 Description. (2014). Rapidly-dividing cells including those in kidney, gastrointestinal tract, immune compartments and cancer cells, possess a tremendous appetite for glutamine. Glutamate antagonists, such as phencyclidine (PCP) and ketamine, are well known to transiently induce symptoms similar to those observed in patients with schizophrenia 6-Diazo-5-oxo-L-norleucine (DON) is a potent glutamine antagonist with toxic side effects; in order to reduce these effects, multiple prodrugs have been designed. A great example of the ambiguousness of glutamate receptor antagonists is gacyclidine. Antagonist Definition. 0354. Drugs that bind to but do not activate histamine receptors, thereby blocking the actions of histamine or histamine agonists. Glutamine metabolism inhibitors include glutamine antimetabolites and their prodrug forms and allosteric glutaminase inhibitors. Classical antihistaminics block the histamine H1 receptors only. , Dugan M. Some oncogenes also rewire tumor cells with distinct glutamine consumption phenotypes. 353. 6-Diazo-5-oxygen-L-deamine, a glutamine antagonist, inhibits glutamine-based enzymes . Glutamate is recycled and made by glial cells in your brain. The inhibition is also completely relieved by cytidine in noncompetitive manner, but not by guanosine or uridine, indicating that the principal damage to the cellular economy This was the only example of a drug that could be given “late” in the disease process, after symptom onset, a common clinical scenario in both pediatric and adult CM. Front. (1975) found that of the seven amidotransferases in- volved in nucleotide metabolism, amidophosphoribosyltrans- ferase, GMP synthetase, carbamyl phosphate synthetase II (glutamine hydrolyzing) were not significantly affected by Glutamine and its metabolites. SLC1A5 (ASCT2) facilitates the passage of glutamine across the membrane. On the one hand, targeted glutamine metabolism inhibits IDO expression in tumour and myeloid cells, significantly decreasing kynurenine levels. Glutamine metabolism is reprogrammed during tumorigenesis and has been investigated as a promising target for cancer therapy. Ongoing research and innovative drug delivery strategies are paving the Learn about DON, a glutamine antagonist that blocks glutamine utilization in cancer cells and has shown efficacy in preclinical and clinical studies. Glutamine levels are also reduced in OPA1 deficient patients. Some of those are in the form of various people, monsters, and situations, but the main antagonist throughout the series remains Lord Voldemort, his sworn enemy. DON is a glutamine antagonist that can inhibit glutamine-using enzymes and block the metabolism of glutamine by irreversibly binding to enzyme active sites [[10], [11], [12]], with early preclinical experiments indicating excellent anti-tumor effects; since 1957, DON has been evaluated in multiple clinical studies [[13], [14], [15]]. In For example, breast cancer cells show systemic differences in glutamine dependence, with basal cells favoring glutamine dependence and luminal cells favoring glutamine independence . Given the significance of glutamine metabolism in cancer, 1 DON was investigated as a chemotherapeutic agent in a Glutamine antagonists, such as 6-diazo-5-oxo-L-norleucine (DON), rescue neurotoxicity and behavioral deficits in disease models where excess glutamate is thought to be pathogenic, including HIV-associated neurocognitive disorders , multiple sclerosis , Rett syndrome , viral infection , and cerebral malaria . Rowling, Potter and his friends come against many obstacles on their journey through the seven books. Gori , 1, 2 Kathryn M. Second, the TME in EGFR mutation-driven lung cancer is poorly immunogenic, The glutamine antagonist such as DON (6-diazo-5-oxo-l-norleucine) found previously is nonspecific, has toxic or side effects, and inhibits several enzymes of glutamine utilization . This study focused on glutamine-metabolising enzymes and transporters to reveal the effect of glutamine on tumour cell metastasis [19]. , Galluccio M. glutaminase, has been shown to block glutamate over-production induced by HIV infection or immune challenge, Download scientific diagram | The glutamine antagonist 6-diazo-5-oxo-L-norleucine is the most effective metabolic inhibitor tested against NBL and Ewing’s sarcoma cell lines. However, tryptophan from food-based sources (like turkey, Glutamine antagonists/analogues including 6-diazo-5-oxo-norleucine (DON), acivicin, and JHU-083, are substances that are highly similar to glu- For example, compound 968 w as . Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer. However, clinical utility was limited due to adverse effects (39–42). Glutamine addiction represents a metabolic vulnerability of cancer cells; however, effective therapeutic targeting of the pathways involved remains to be realized. Lemberg , 1, 3 Arindom Pal , 1, 2 Vijayabhaskar Veeravalli , 8 Ying Wu , 1 Joanna M. Grape juice contains moderate levels of glutamate. Glutamine antagonist DRP-104 in combination with durvalumab in patients with advanced fibrolamellar carcinoma (FLC) following progression on prior anti-PD(L)1 therapy. Targeting each step of glutamine metabolism has shown promising results in Here, the authors report that JHU083, an orally active glutamine antagonist prodrug designed to be preferentially activated in the tumor microenvironment, has potent anticancer effects on EGFR Glutamine antagonists and their use for treating oncological, immunological, and neurological diseases are disclosed. for example, leucine through distinct mechanisms, 20,32 and through intracellular purine and pyrimidine nucleotide levels. When compared to chronic epilepsy, it is distinguished by the durability of seizures and frequent resistance to benzodiazepine (BZD). a, Diagram illustrating broad inhibition of glutamine metabolism by the glutamine antagonists DON or DRP-104. Our findings were consistent with multiple studies demon-strating that glutamine antagonists exhibit promise as neuro-protective agents. For example, deprivation of glutamine induces necrosis of intestinal mucosa and apoptosis in human cell lines (12, 18), while additional oral supplementation of glutamine among cancer Citation 51 For example, hypoxia induces GLS expression. Transfer of glutamine from astrocytes to neurons is of fundamental importance for maintaining the proper function of glutamatergic neurotransmission (Schousboe et al. The antitumor activity of the glutamine antagonist JHU083 against urologic tumors is myeloid dependent. K. MCT-20-0354; Background Tumor metabolism is emerging as a regulator of immune mediated anti-tumor responses. Drugs such as ebselen, chelerythrine and apomorphine were also regarded as GLS inhibitors in a recent research . Glutamine provides fuel for rapidly dividing cells, including tumour cells and lymphocytes For example, at 10 microM each of L-SMETH and Cu2+, almost complete growth inhibition was observed if cells were grown in 1 mM glutamine, 50% inhibition at 2 mM glutamine, and none at 4 mM glutamine. , Scalise M. Recently, DRP-104 (sirpiglenastat), a prodrug of DON, was developed as a new cancer agent with reduced toxicity as its activation is dependent on two enzymatic reactions occurring in the For example, the broadly active glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) was investigated in the 1950s as an anticancer agent across multiple malignancies including prostate cancer, but phase I-II trials were hampered by dose-limiting gastrointestinal (GI) toxicities resulting in abandonment of its clinical development . Glutamine metabolism is one of the hallmarks of cancers which is described as an essential role in serving as a major energy and building blocks supply to cell proliferation in cancer cells. B, Violin plots showing the expression levels and fractional abundance of Cerebral malaria is the most deadly complication associated with P. This was the only example of a drug that could be given “late” in the disease process, after symptom onset, a common clinical scenario in both pediatric and adult CM. The mixed solution should be used immediately for optimal results. 6-Diazo-5-oxo-l-norleucine (DON), a glutamine antagonist, previously showed promising antitumor effects . A simple example of an antagonist is the Queen in Snow White and the Seven 14. The present review addresses how stereochemistry affects the activity of glutamate receptor ligands. E. Cartoon representation of the human NMDA receptor. We performed cell growth, cell cycle, Inhibiting glutaminolysis, coupled with chemo medications or other metabolic inhibitors, triggers synergy drug combinations in glutamine-dependent tumors. presented a multifunctional intelligent nanoplatform CuO2@mPDA/DOX-HA (CPPDH), which induced the consumption of GSH and the self-supply of H2O2 (72). One hundred years have passed since Warburg discovered alterations in cancer metabolism, more than 70 years since Sidney Farber introduced anti-folates that transformed the treatment of childhood Several types of ionotropic glutamate receptors have been identified. August 2021; Bioorganic & Medicinal Chemistry Letters 50(9):128321; The glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON,1) has shown robust anti-cancer efficacy in preclinical and clinical studies, but its development was halted due to marked systemic toxicities. ado7808. Memantine is one of the approved medications for moderate to severe Alzheimer’s disease. At the same time, we focused on the role of glutamine in tumour metastasis and the influence on and mechanism of glutamine metabolism in tumour By contrast, there are many examples of achiral competitive antagonists. 11C). green tea: contains EGCG, which inhibits an enzyme, glutamate dehydrogenase, that helps cancer cells use glutamine; ashwaghanda: contains the enzyme L-asparaginase, DON is a powerful glutamine antagonist with the potential to starve cancer cells and inhibit their growth. However, there are currently no reports of a DON prodrug with a defined mechanism to achieve high tumor selectivity. DON is not Within the tumour microenvironment (TME) there is a cellular ‘tug-of-war’ for glutamine, the most abundant amino acid in the body. Glutamate is also needed for making another neurotransmitter in your brain called gamma-aminobutyric acid (GABA). , Indiveri C. 32 31. As a “conditionally essential amino acid,” glutamine contributes to the growth and proliferation of AML cells. A 100 gram serving has 250 milligrams of glutamate, which is about ⅔ of a cup. B) The glutamine antagonist 6-diazo-5-oxo-norleucine (DON) inhibits growth of MPNST cells with IC50 over 3-fold less than for control cells. Aguilar , 1 Ranjeet P. Lord Voldemort. The physiological relevance of the glutamine-glutamate cycle has been unclear. (A) In glutamine-replete condition, glutamine is used for many biosynthetic and non-biosynthetic purposes (grey boxed arrow), which together contribute to tumor cell proliferation. Clin. a glutamine analog and antagonist, had long been recognized for its antitumor properties 6 , but clinical use was hampered by intoler- able gastrointestinal toxicity. The goal of his review is to discuss some of the glutamate-glutamine cycle components that are altered in epilepsy, particularly neurotransmitters and metabolites, enzymes, amino acid transporters, and glutamate receptors. Introduction. Drug Drug Description; During growth and proliferation, T cells preferentially use glutamine instead of glucose as an energy source, and rapidly dividing activated T cells show increased glutamine uptake and metabolism (Carr et al. 6 million cancer fatalities are expected in 2022, with 350 deaths a day from lung cancer, the biggest cause of cancer mortality . In fact, glutamine was recognized as the most abundant free amino acid found in the human muscles and in plasma. 008 Glutamine antagonist JHU083, decreases IL-10-producing MDSCs leading to a higher frequency of activated T-cells. The use of a glutamine antagonist, such as 6-diazo-5-oxo-L-norleucine, for treating cerebral edema and restoring blood-brain barrier integrity, such as in patients suffering from cerebral The present study highlights the therapeutic potential of the well-tolerated, brain penetrable glutamine antagonist JHU-083, as a novel treatment for both the physical and cognitive deficits of MS. Eric Plitman, Ariel Graff-Guerrero, in European Neuropsychopharmacology, 2014. Glutamine provides anaplerotic nitrogen and a carbon source for many macromolecule syntheses to support cancer cell growth. 1. Request PDF | On Jan 3, 2022, Gui Chen and others published Glutamine Antagonist Synergizes with Electrodynamic Therapy to Induce Tumor Regression and Systemic Antitumor Immunity | Find, read and In recent years, an increasingly more in depth understanding of tumor metabolism in tumorigenesis, tumor growth, metastasis, and prognosis has been achieved. Top Antagonist Examples 1. Within the tumour microenvironment (TME) there is a cellular ‘tug-of-war’ for glutamine, the most abundant amino acid in the body. 2 9. H. Treatment of glioblastoma multiforme (GBM) remains challenging. Interestingly, clinical studies report that memantine decreased the positive subjective effects of cigarette smoking and intravenous heroin in human subjects (Comer and Sullivan, 2007 ; Jackson et al. Glutamate is then converted to α-KG by GLUD1 or other mitochondrial aminotransferases, such as GPT2 and GOT2. Proliferating cancer cells rely largely on glutamine for survival and proliferation. Slusher, Rais, Majer and Powell are founders and hold equity in Dracen Pharmaceuticals Inc. Other glutamine metabolism antagonists (such as ASCT2 antagonist) have also shown antitumor activity in preclinical models (Stine et al. For example, glutamine plays an indispensable For example, glutamine is converted to glucose if your body needs more glucose as an energy source. 1. Scheffler M. As a result, cancer researchers are working to find drugs that block SLC1A5 and The glutamine antagonist DRP-104 blocks purine synthesis and combines with checkpoint inhibitors to promote antitumor immunity in KEAP1/NRF2-mutant lung cancers. The brain contains a very high concentration of glutamate ranging from 80 to 100 nmol/mg protein (i. For example, immunosuppressive This was the only example of a drug that could be given “late” in the disease process, after symptom onset, a common clinical scenario in both pediatric and adult CM. Methods: Splenic-derived T cells and bone Identification and Characterization of IMD-0354 as a Glutamine Carrier Protein Inhibitor in Melanoma. Membrane transporters for the special amino acid glutamine: structure/function relationships and relevance to human health. It may be that glutamine antagonism in cancer cells indirectly induces other changes in the tumor microenvironment, for example, improved pH and enhanced nutrient availability, that culminate in cytotoxic T cell stimulation . 5–4 μM in the extracellular fluid of the brain. Pancreatic ductal adenocarcinoma (PDAC) cells use glutamine (Gln) to support proliferation and redox balance. 1126/sciadv. Glutamine serves as a carbon source for the synthesis of lipids and metabolites via the TCA cycle, as well as a Memantine. Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year overall survival rate of approximately11% 1,2. However, clinical utility was limited due to adverse effects ( 39 – 42 ). A compound developed by Johns Hopkins researchers that blocks glutamine metabolism can slow tumor growth, alter the tumor microenvironment and promote the production of durable and highly active anti-tumor T cells. The “kidney-type” glutaminase (GLS1) is a metabolism enzyme which plays a significant part in glutaminolysis. DRP-104 is inactive in its prodrug form with high plasma and GI tissue stability. Gamma-aminobutyric acid (GABA) inhibitors, or GABA antagonists, are drugs that inhibit the action of GABA, the primary inhibitory neurotransmitter of the central nervous system. These glutamate receptors are named after the agonists that activate them: NMDA (N-methyl-D-aspartate), AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate), and kainic 6-Diazo-5-oxo-l-norleucine (DON, Fig. 1158/1535-7163. , 2010, Maciolek et al. Jančařík A, Prchalová E, Zimmermann SC, Dash RP, et al. For example, Jayaram et al. Blum7,8, Ali Rashidfarrokhi1, Shih Ming Huang1, Christian Bahamon1, Warren L. , 2014). Recently, DRP-104 (sirpiglenastat), a prodrug of DON, was developed as a new cancer agent with reduced toxicity as its activation is dependent on two enzymatic reactions occurring This brief video featuring Mark Yarchoan, MD and Marina Baretti, MD of John Hopkins University describes the rationale and structure of a new clinical trial Abstract. Early attempts to inhibit Gln metabolism using glutaminase In this study, we tested the hypothesis that the brain penetrant glutamine antagonist prodrug JHU-083 reduces glioma cell growth. 2020 DOI: 10. . Previously, we reported increased infiltration of immunosuppressive tumor associated macrophages (TAMs) with disease progression in prostate adenocarcinoma. Objective: To measure the impact of JHU-083, a novel prodrug of the glutamine antagonist 6-diazo-5-oxo-l-norleucine, on immune cell proliferation and activation, along with physical and cognitive impairments associated with the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Yet another example of an enzyme contributing to the oxidative capacity of cancer cells is GDH1, which could serve as a potential treatment target . For example, immunosuppressive Antagonist Examples Are the Key to Storytelling Success Studying antagonist examples in literature and film will help you understand the depth and diversity of these pivotal characters. Compounds such as DON (6-Diazo-5-oxo-L-norleucine), acivicin, and azaserine have been shown to inhibit the growth of a variety of cancers in various clinical studies [ 17 ]. Hanaford*, Jesse Alt †, Rana Rais For example, at 10 microM each of L-SMETH and Cu2+, almost complete growth inhibition was observed if cells were grown in 1 mM glutamine, 50% inhibition at 2 mM glutamine, and none at 4 mM glutamine. For example, immunosuppressive myeloid cells overexpress arginase, scavenging arginine and . GABA receptors categorize into the GABA-A receptor and GABA-B receptor subtypes. B. The study presented a full and comprehensive comprehending of the glutamine metabolism atlas and heterogeneity in GBM for facilitating the development of a more effective therapeutic choice. For example, lung cancer with epidermal growth factor receptor (EGFR) Thus, combining EVax with JHU083, an orally bioavailable glutamine antagonist prodrug will provide optimal efficacy to prevent EGFR-driven lung cancer development and progression. The Receptor Trafficking Hypothesis, which suggests that the downregulation of γ-Aminobutyric acid type A (GABAA) receptors, and upregulation of N DRP-104 is a prodrug of the broad acting glutamine antagonist DON (6-Diazo-5-oxo-L-norleucine). N-(Pivaloyloxy)alkoxy-carbonyl prodrugs of the glutamine antagonist 6-Diazo-5-oxo- l -norleucine (DON) as a potential treatment for HIV associated neurocognitive disorders. The broadly active glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) has shown potent tumor toxicity and tremendous therapeutic efficacy across several indications (22, 23). Glutamine/glutamate/aKG have been shown to support mitochondrial oxidative phosphorylation in brain mitochondria from Ndufs4 deficient mice where significant defects in ETC CI driven mitochondrial oxygen consumption are seen with other metabolic substrates, such as pyruvate and lactate. Example traces and corresponding paired sample data (analyzed by Student’s t test) show the effect of 1 mM γ-DGG applied for 6 min . Orally bioavailable DON prodrugs provide a path for clinical development of glutamine antagonists for use in pediatric patients. In gliomas, the most common type of brain tumors, metabolic reprogramming leads to abnormal consumption of glutamine as an energy source, and increased glutamine concentrations are associated with treatment resistance and proliferation. Wu 1, Benefitting from the marvelous potential of reactive oxygen species (ROS)-mediated dynamic therapies in tumor immunocombination therapy due to their immunogenic cell death (ICD) effect, a glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON)-loaded nanocarrier (Pt-Pd@DON) was designed for combination therapy (EDT and immunotherapy) against Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma1,2 Allison R. WO2019071110A1 - NOVEL GLUTAMINE ANTAGONISTS AND USES THEREOF - Google Patents NOVEL GLUTAMINE ANTAGONISTS AND USES THEREOF Download PDF Info Publication number WO2019071110A1. Inhibition of GLS with CB-839, or of glutamine metabolism broadly with JHU083 or DRP-104 (Sirpiglenastat, another pro-drug of DON), restores balance between tumor and T-cell glutamine utilization. Combination of glutaminase inhibitor CB-839 and ASCT2 inhibitor V-9302 showed efficient antitumor effect against glutamine addicted liver cancer cells via glutathione depletion and reactive oxygen species (ROS) induction. for example, improved pH and enhanced nutrient availability, that For example, Xiao et al. Glutamine antagonist JHU083, decreases IL-10-producing MDSCs leading to a higher frequency of activated T-cells. For example, immunosuppressive myeloid cells overexpress arginase, The recent success of L-asparaginase in the therapy of certain human neoplasms has prompted a reconsideration of the compounds that can alter L-glutamine metabolism, because L-glutamine is necessary, in most mammalian systems, for the synthesis of L-asparagine, both azaserinc and azotomycin appear to be synergistic with L-asparaginase A compound developed by Johns Hopkins researchers that blocks glutamine metabolism can slow tumor growth, alter the tumor microenvironment and promote the production of durable and highly active Compositions of dendrimers conjugated with one or more glutamine antagonist(s) that inhibit glutamine metabolism, preferably in activated microglia, and methods of use thereof for treating, alleviating, and/or preventing one or more neurological, oncological, and/or immune disorders associated with pathogenic or dysregulated glutamine-dependent pathways and/or 6-Diazo-5-oxo- l -norleucine (DON) is a glutamine antagonist that suppresses cancer cell metabolism but concurrently enhances the metabolic fitness of tumor CD8 ⁺ T cells. Discover how JHDD has developed DON prodrugs that selectively deliver DON to Tumors often achieve this by pumping increasing levels of the amino acid glutamine into their cells, primarily through a pump called SLC1A5. [1] A GABA-C receptor also exists, but it is typically Most of these amidotransferases are inhibited by all three glutamine antagonists in uitro. , et al. For simplification, we listed signaling, TCA cycle, NEAAs and nucleotides as key components mediating glutamine-dependent cell proliferation. Recently, DRP-104 (sirpiglenastat), a prodrug of DON, was developed as a new cancer agent with reduced toxicity as its activation is dependent on two enzymatic reactions occurring in the Status epilepticus (SE) is a neurological emergency with a high mortality rate. All NMDARs contain two of the obligatory GluN1 subunits, which when assembled with The glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON, 14), which is known to inhibit glutaminase, has been shown to block glutamate over-production induced by HIV infection or immune challenge, and to mitigate excitotoxic neuronal damage both in vitro and in vivo, 13,39–41 but has not yet been tested in an animal model of HAND. Targeting glutamine metabolism is beneficial for reducing tumour metastasis. Notably, it is also shown that environmental cystine can dictate glutamine dependence and anaplerosis in A549 NSCLC cells [ 124 , 125 ]. DON creates a metabolic crisis in pancreatic cancer a, As Gln has pleiotropic roles in cellular metabolism, we hypothesized that using a broad-acting Gln antagonist, such as DON or DRP-104, could The glutamine antagonist DRP-104 blocks purine synthesis and combines with checkpoint inhibitors to promote antitumor immunity in KEAP1/NRF2-mutant lung cancers. Glutamine-target strategies as new treatment approaches have been widely explored in AML treatment to Another non-competitive NMDA antagonist known as MK-801 has also been marred by contradictory data. 2017;60(16):7186–7198. Glutaminase is an enzyme that converts glutamine into glutamate, a secondary fuel for cancer cells. Phase 1 and phase 2a, first-in-human (FIH) study, of DRP-104, a broad glutamine antagonist, in adult patients with advanced solid tumors. JHU083 treatment was associated with lower lung levels of quinolinic acid suggesting a corresponding reduction in the immunosuppressive metabolite kynurenine (Kyn). Glutamine antagonists have shown potential Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer Ray Pillai1,2,3†, Sarah E. Dash , 1, 2 Lukáš Tenora , 9 Pavel Majer , 9 Qi Sun , 10 Barbara S. , Lafleur F. Taking the 1 mL working solution as an example, add 50 μL of 14 mg/ml clear DMSO stock solution to 950 μL of corn oil and mix evenly. Hanaford*, Jesse Alt †, Rana Rais Among the 20 amino acids detailed in the genetic code, glutamine provides the best example of the versatility of amino acid metabolism and immune function. Inhibition of glutamine-using reactions including GLS halts proliferation of rapidly proliferating cells that are dependent on glutamine and curtails synthesis of the Glutamine provides a source of carbon and nitrogen needed for nucleotide synthesis, and targeting glutamine metabolism with the glutamine antagonist 6-diazo-5-oxo-norleucine (DON) might be used in A brain penetrant glutamine antagonist prodrug, JHU-083, extends survival in an intracranial model of IDH mutant glioma. As a result, cancer researchers are working to find drugs that block SLC1A5 and reduce glutamine levels. Glutamine deprivation can lead to rapid activation of Caspase-9, which is the main promoter caspase that activates apoptosis in GLN-deprived cells. These patents have been licensed to Dracen Pharmaceuticals Inc. J. The Gln metabolism in PCa is tightly controlled by well-described This brief video featuring Mark Yarchoan, MD and Marina Baretti, MD of John Hopkins University describes the rationale and structure of a new clinical trial For example, cell death is often determined after 24 h. Under conditions of nutrient starvation, glutamine can also be acquired through the autophagic break-down of macromolecules [1,16]. Slusher, Rais, Tenora, Majer, Alt and Powell are inventors on Johns Hopkins University patents covering novel glutamine antagonist prodrugs described in this research. Using a glutamine antagonist, we metabolically dismantled the immunosuppressive microenvironment of tumors. To improve the selec As such, we have developed a prodrug of the glutamine antagonist DON, which not only inhibits GLS, but also all other glutamine-requiring reactions important to tumor growth, including purine and pyrimidine biosynthesis, redox control, glycosylation, amino acid and collagen synthesis, autophagy, and epigenetic modification (3, 21). , approximately 10 mM) depending on the region (Erecinska and Silver, 1990). Isocitrate Dehydrogenase | Find, read and cite all the research you Cells were serum and glutamine starved for 24 h to deplete intracellular glutamine stores; infected with NSV at multiplicities of infection (MOIs) of 1 and 10; and cultured in either complete medium (DMEM, 1% dialyzed FBS, 2 mM glutamine, Pen-Strep), glutamine-deficient medium (DMEM without glutamine, 1% dialyzed FBS, Pen-Strep), or complete medium 6-Diazo-5-oxo-l-norleucine (DON, Fig. Juice. IC50 (µ M) ipn02. Metabolic heterogeneity is not only found in tumor cells but also in their surrounding immune glutamine transporters, glutaminase, aminotransferase, and redox homeostasis are essential for cancer cell survival6. Glutamine metabolism in tumor microenvironments critically regulates antitumor immunity. For example, Xiao et al. , 2021). This competition is most evident when considering the balance Glutamine (Gln) is converted to glutamate However, whereas mGluR2/mGluR3 antagonists (for example, LY341495 and MSG0039) appear to have antidepressant-like properties, Examples include: AMPA; Glutamic acid; Ibotenic acid; Kainic acid; N-Methyl-D-aspartic acid; Quisqualic acid; See also. WO2019071110A1 PCT This was the only example of a drug that could be given “late” in the disease process, after symptom onset, a common clinical scenario in both pediatric and adult CM. Cancer is the leading cause of mortality globally . Three of these are ligand-gated ion channels called NMDA receptors, AMPA receptors, and kainate receptors (Figure 7. Also disclosed are methods for treating an oncological, immunological, infectious or neurological disease or disorder, the method comprising administering to a subject in need of treatment thereof a therapeutically effective amount of a glutamine antagonist of the Novel Glutamine Antagonist JHU395 Suppresses MYC-Driven Medulloblastoma Growth and Induces Apoptosis Khoa Pham , MD, 1 Micah J Maxwell , MD, PhD, 2 Heather Sweeney , 2 Jesse Alt , BS, 3 Rana Rais , PhD, 3, 4 Charles G Eberhart , MD, PhD, 1, 5 Barbara S Slusher , PhD, 3, 4 and Eric H Raabe , MD, PhD 1, 2, 5 ES2930258T3 ES18864999T ES18864999T ES2930258T3 ES 2930258 T3 ES2930258 T3 ES 2930258T3 ES 18864999 T ES18864999 T ES 18864999T ES 18864999 T ES18864999 T ES Here we show that a novel glutamine metabolism antagonist, JHU083, 36. In addition to direct anti-tumor efficacy, Scientists at Sanford Burnham Prebys Medical Discovery Institute have identified a drug candidate that blocks the uptake of glutamine, a key food source for many tumors, and We investigated glutamine dependence of MPNST using JHU395, a novel orally bioavailable GA prodrug designed to circulate inert in plasma, but permeate and release active GA within In this study, we tested the hypothesis that the brain penetrant glutamine antagonist prodrug JHU-083 reduces glioma cell growth. Given the significance of glutamine metabolism in cancer, 1 DON was investigated as a chemotherapeutic agent in a We previously showed that KEAP1 mutant tumors consume glutamine to support the metabolic rewiring associated with NRF2-dependent antioxidant production. The Receptor Trafficking Hypothesis, which suggests that the downregulation of γ-Aminobutyric acid type A (GABAA) receptors, and upregulation of N Glutamine metabolism in tumor microenvironments critically regulates antitumor immunity. The review focuses mainly on agonists and discusses stereochemical and conformational considerations as well as biostructural knowledge of the agonist binding pockets, which is useful in the design of Relapse after chemotherapy and hematopoietic stem cell transplantation leads to adverse prognosis for acute myeloid leukemia (AML) patients. Corresponding IC50 values listed in table. While these types of studies have been shown to be very useful for understanding the pathways involved in acute excitotoxicity, it has proven much more difficult to study chronic excitotoxicity in culture partly because it is not entirely clear how to define “chronic” in the context of cell culture. Slusher , 1, 7, * Model Studies towards Prodrugs of the Glutamine Antagonist 6-Diazo-5-oxo-L-norleucine (DON) Containing a Diazo Precursor. Glutaminase Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma1,2 Allison R. The glutamine antagonist DON and its precursor JHU-083 inhibit tumor cell proliferation via inhibition of the activity of a variety of enzymes that are required for tumor glutamine metabolism. The broad heterogeneity in tumor tissue is the critical factor affecting the outcome of tumor treatment. J Med Chem. This competition is most evident when considering the balance DRP-104 is a prodrug of the broad acting glutamine antagonist DON (6-Diazo-5-oxo-L-norleucine). Telaglenastat (CB-839) is a first-in-class, potent and selective DON (6-Diazo-5-oxo-L-norleucine) is an irreversible inhibitor of several enzymes that utilize glutamine as a metabolic substrate. For example, AMPAR blockade consistently prevents the antidepressant-like effects of ketamine and other putative NMDAR antagonists in animal models 49,80,82,83, and recent data suggest that As such, we have developed a prodrug of the glutamine antagonist DON, which not only inhibits GLS, but also all other glutamine-requiring reactions important to tumor growth, including purine and pyrimidine biosynthesis, redox control, glycosylation, amino acid and collagen synthesis, autophagy, and epigenetic modification (3, 21). In the Harry Potter series by J. What is an antagonist? Here’s a quick and simple definition: An antagonist is usually a character who opposes the protagonist (or main character) of a story, but the antagonist can also be a group of characters, institution, or force against which the protagonist must contend. JHU395 is an orally-bioavailable and a plasma stable lipophilic glutamine antagonists (GA) proagent. Status epilepticus (SE) is a neurological emergency with a high mortality rate. com to learn about our seamless integration into healthcare software. A 12-ounce glass of grape juice will contain over 500 Sirpiglenastat (DRP-104) is a broad acting glutamine antagonist. MeSH list of agents 82018690; This page was last edited on 27 November 2021, at The presently disclosed subject matter provides methods for quantifying levels of glutamine antagonists, such as 6-diazo-5-oxo-L-norleucine (DON), including such glutamine antagonists resulting from in vivo conversion of ester prodrugs of such glutamine antagonists, in a Results: After 24 hours, the results showed that the ketamine group had a significant decrease in their depression symptoms. Competitive antagonists such as CGS-19755 have been shown to have limited clinical utility because of poor penetration of the blood-brain barrier. For example, kidneys primarily use glutamine to drive anaplerosis and maintain pH balance , whereas muscles and adipose tissue largely promote de novo glutamine synthesis [122,123]. , 2009 ). Memantine blocks the effects of sustained, pathologically elevated levels of glutamate that may otherwise lead to neuronal dysfunction []. Molecular Cancer Therapeutics, 2021; molcanther. A, Dot plots showing expression levels and fractional abundance of myeloid cells expressing glutamine metabolism enzymes, GLUL, and GLS across samples (tumor, involved, distal, and benign). Glutamate-mediated excitotoxicity in schizophrenia: A review. antagonist, suggested to us that Mtb may employ its extracellular GlnA1 enzyme as a virulence factor to increase Gln metabolism in the granuloma microenvironment, thereby creating an immunosuppres- Glutamine metabolism, synthesis, and regulation by oncogenes. 6-Diazo-5-oxo-L-norleucine (L-DON), azaserine, and acivicin are glutamine antimetabolites and ethyl 2-(2-amino-4-methylpentanamido)-DON (JHU083) is a prodrug form of L-DON that is selectively activated in the tumor microenvironment. JCO 42 , TPS573-TPS573 (2024). Clinical studies of DON in the 1950s using low daily doses suggested antitumor activity, but later phase I and II trials of DON given intermittently at high doses were hampered by dose-limiting nausea and For decades, researchers have been searching for ways to develop effective glutamine antagonists that block glutamine metabolism in cancer cells [76,77,78,79,80]. It has also been shown that turning off the gene which produces this glutamine transporter has anti-cancer effects in cell models. The present study highlights the therapeutic potential of the well-tolerated, brain penetrable glutamine antagonist JHU-083, as a novel treatment for both the physical and cognitive deficits of MS. α-KG can then enter the TCA US11110104B2 US15/884,974 US201815884974A US11110104B2 US 11110104 B2 US11110104 B2 US 11110104B2 US 201815884974 A US201815884974 A US 201815884974A US 11110104 B2 US11110104 B2 Glutamine is an amino acid found in both animal and plant protein; it is the most abundant amino acid in the human body - it is non-essential, you make it yourself in your muscles from where it supplies other organs; 25% is found in your brain. Glial cells convert “used” glutamate to glutamine, which is converted back again into glutamate when delivered back to the terminal area of nerve cells. The broadly active glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) has been studied for 60 years as a potential anticancer therapeutic. Functional NMDA receptors are heterotetramers comprising different combinations of the GluN1, GluN2 (A-D), and GluN3 (A-B) subunits derived from distinct gene families (Grin1-Grin3). Acivicin is an L-glutamine antagonist which underwent phase II clinical efficacy evaluation as an anticancer drug in 1985–1986. Glutamine is largely obtained through the diet but can also be synthesised de novo through activity of glutamine synthase []. Presented here are structures of glutamine (left) and glutamate (right) — respective Effect of glutamine antagonists on cancer cell metabolism and the immune microenvironment. concentrations of glutamine added back to glutamine-free media to rescue growth compared to immortalized Schwann cells. Many malignant tumor cells always display glutamine addiction. DON is not Hence, manipulations of discrete glutamate-glutamine cycle components may represent novel approaches to treat the disease. doi: 10. Proposed models of the effect of JHU083 on the heterogeneous tumour microenvironment by blocking tumour glutamine metabolism. It is a non-competitive antagonist of NMDA receptor, one of the main receptors of glutamatergic system []. Drug Drug Description; Visit DrugBank. Slusher also serves as a scientific Benefitting from the marvelous potential of reactive oxygen species (ROS)-mediated dynamic therapies in tumor immunocombination therapy due to their immunogenic cell death (ICD) effect, a glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON)-loaded nanocarrier (Pt-Pd@DON) was designed for combination therapy (EDT and immunotherapy) against SUMMARY: The glutamine pathway is emerging as an important marker of cancer prognosis and a target for new treatments. This is highlighted by the fact that during neurotransmission glutamate is taken up by astrocytes via the efficient high affinity glutamate transporters of the 6. 1 Glutamine metabolism has been implicated in immunosuppressive TAMs as well as mCRPC2 and Glutamine antagonists have a long history of use. Clinical studies of DON in the 1950s using low daily doses suggested antitumor activity, but later phase I and II trials of DON given intermittently at high doses were hampered by dose-limiting nausea and vomiting. We here demonstrate that oral JHU-083 provides robust delivery of DON into diverse brain regions in the mouse as well as significant activity against multiple models of MYC-driven medulloblastoma. Some studies have been able to see a neuroprotective effect [123-128] and others have not [129-131]. Thereafter, glutamine is converted to glutamate by GLS, and NH 3 is released. 5-HTP: Your body converts 5-HTP into serotonin, and serotonin can enhance GABA activity. Inhibition of glutamine-using reactions including GLS halts proliferation of rapidly proliferating cells that are dependent on glutamine and curtails synthesis of the excitotoxic GLS product Antagonists of the NMDA receptor act either by competitive antagonism at the glutamate-binding site or by noncompetitive antagonism at the glycine, phencyclidine (PCP)-, and magnesium-binding sites. Here, using preclinical patient-derived xenograft models and antigenic orthotopic lung cancer models, we show that the glutamine antagonist prodrug DRP-104 impairs the growth of KEAP1 mutant Glutamine antagonist DRP-104 in combination with durvalumab in patients with advanced fibrolamellar carcinoma (FLC) following progression on prior anti-PD(L)1 therapy. We show JHU Glutamine antagonists, such as 6-diazo-5-oxo-L-norleucine (DON), rescue neurotoxicity and behavioral deficits in disease models where excess glutamate is thought to be pathogenic, including HIV-associated neurocognitive disorders , multiple sclerosis , Rett syndrome , viral infection , and cerebral malaria . Wu 1, Loading Loading Glutamine metabolic compartments have emerged as promising candidates, especially in TNBC and drug-resistant breast cancer. LeBoeuf1†, Yuan Hao 4,5, Connie New6, Jenna L. For example, early in vivo animal experiments showed that glutamine was essential for the production of cytokines (such as IL-1, IL-6, TNFα), antigen presentation, and Glutamine antagonism, for example, by intervening in glutamine utilization in specific subsets of cancer cells that exhibit glutamine addiction. Using the glutamine-antagonist prodrug JHU083, we report potent tumor growth inhibition in urologic tumors SummaryAmyotrophic lateral sclerosis (ALS) is a degenerative neurological disorder that is manifested clinically by muscle weakness, wasting, spasticity and bodyweight loss, typically resulting in death from debilitating disease within 2 to 5 years of the onset of symptoms. 3. 1) is a glutamine analog that acts on a broad range of glutamine-utilizing enzymes by forming a covalent bond with a nucleophilic residue at an active site, resulting in the irreversible inhibition of the enzymes. Glutamine Antagonist GA-607 Causes a Dramatic Accumulation of FGAR which can be used to Monitor Target Engagement Jesse Alt , 1 Sadakatali S. designed a biomimetic immune metabolism nanoplatform that encapsulated a new photosensitizer and a glutamine metabolism antagonist in the cancer cell amino acids, the most flexible substances in the body, have more complex and diverse physiological functions. There were also no reported side-effects of the ketamine. For example, lung cancer with epidermal growth factor receptor (EGFR)‐activating mutations exhibit elevated glutamine metabolism. Glutamine is the most abundant and versatile amino acid in the body, and is of fundamental importance For example, the FDA has approved memantine, a non-competitive NMDA antagonist, for the treatment of Alzheimer's disease (Cummings, 2004). α-KG can then enter the TCA The glutamine antagonist DRP-104 blocks purine synthesis and combines with checkpoint inhibitors to promote antitumor immunity in KEAP1/NRF2-mutant lung cancers. falciparum infection, having a fatality rate of 15-25% in African children despite the use of effective antimalarial chemotherapy. They are the shadows shaping stories, the hurdles our heroes overcome, and the mirrors reflecting our own fears and aspirations. 3. Mechanism of glutamine antagonist JHU083 enhancing antitumour immunity. Glutamine antagonists may KEAP lung cancer in check Sci Adv. RR and BSS are inventors on Johns Hopkins University patents covering novel glutamine antagonist prodrugs: “Prodrugs of glutamine analogs” (WO2017023774A1); Keywords: glutamine, cancer, glutaminase, natural compounds. bioRxiv. Drugs. The concentration of glutamate has been estimated to be 1–10 μM in the CSF and 0. gkcp gpq vorc jxgbb dwauh wfzb zxtxp mnwmps idox toy