JHU083 / Johns Hopkins University, AstraZeneca - LARVOL DELTA

Metabolic cell competition in the glioblastoma tumour microenvironment: glucose, glutamine, and lactate as determinants of immune exclusion and targets for pharmacological reprogramming. (PubMed, Front Oncol) - "Glioblastoma (GBM) remains the most lethal primary brain tumour, with median overall survival of 14 to 16 months despite maximal safe surgical resection, concurrent chemoradiotherapy, and adjuvant temozolomide...Disrupting glucose and glutamine metabolism through glutamine antagonism (DON and prodrugs JHU083/JHU395), dichloroacetate (DCA)-mediated PDK inhibition, intravenous pharmacological ascorbate-mediated GAPDH inactivation and HIF-1alpha destabilisation, systemic glucose restriction (SGLT2 inhibitors), sodium phenylbutyrate-mediated glutamine depletion, and monocarboxylate transporter inhibition can invert this competitive hierarchy, reprogramming the immunosuppressive myeloid compartment while preserving T cell fitness; mebendazole is additionally reviewed as a multi-target anti-parasitic repurposing candidate with demonstrated GBM preclinical survival benefit...GBM cells and immunosuppressive myeloid cells are proposed to constitute a substrate-dependent..."

Journal • Review • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • GAPDH • HIF1A • NLRP3

Reprogramming macrophage immunometabolism via glutamine antagonism potentiates colorectal cancer therapy in mice. (PubMed, Nat Commun) - "In vivo, T17 controls tumor growth better than JHU-083 via macrophage-dependent pathways, and also increases the efficacy of immunotherapy, chemotherapy and anti-angiogenic therapy in female mice carrying subcutaneous CRC tumors. Our findings thus hint T17 as a promising treatment strategy for CRC by targeting macrophage glutamine metabolism to reverse immune suppression."

Journal • Preclinical • Colorectal Cancer • Oncology • Solid Tumor

Glutamine Metabolic Blockade Reprograms the Tumor Immune Microenvironment in Triple-Negative Breast Cancer (SNMMI 2026) - "DRP-104 (Sirpiglenastat), a prodrug of 6-diazo-5-oxo-L-norleucine (DON) with markedly reduced GI toxicity, is a potent glutamine antagonist currently being tested in clinical trials...Using a newly developed immuno-PET probe – [89Zr]-deferoxamine (DFO)-H1.2F3 (anti-murine-CD69 monoclonal antibody, Edwards KJ, et al... Our data strongly suggest that glutamine metabolic blockade differentially impacts MDSC vs. T cells, changing both the abundance and functional state of immune cells. In particular, JHU083 treatment depletes MDSCs and restores effector T-cell activity, shifting immune populations from an immunosuppressive, pro-tumor state to an immune-active, anti-tumor state."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD69 • CD8 • GZMB • IFNG

Single-cell RNA sequencing reveals that host Glutamine Metabolism Inhibition Enhances Macrophage Phagocytosis of Mycobacterium tuberculosis. (PubMed, bioRxiv) - "Additionally, JHU083-treatment also improved phagocytic activity of macrophages, as measured by using fluorescent E. coli as a bait. In conclusion, JHU083-mediated glutamine metabolism inhibition metabolically reprograms macrophages, increasing both their lipid utilization as well as phagocytic activity, potentially driving their antimycobacterial activity that we had observed earlier."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Alpha-Ketoglutarate is a master regulator of epigenetic reprogramming in pancreatic ductal adenocarcinoma progression (AACR 2024) - "Epigenetic and phenotypic changes were not as apparent after treatment with CB839, a glutaminase 1 inhibitor, suggesting that broad inhibition of glutamine metabolism is necessary for chromatin restoration. Together, these data suggest that decreasing AKG in PDAC distant metastasis cells, through glutamine deprivation or JHU083, leads to chromatin changes that specify less malignant phenotypes, providing a rationale for targeting glutamine metabolism as a therapy for late-stage PDAC. *APF and MM are co-corresponding authors."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

Co-targeting asparagine and glutamine metabolism is a viable treatment strategy for PI3K/PTEN mutated cervical cancer (AACR 2024) - "Treatment with glutamine antagonists (DON, JHU-083) and GLS inhibitors (CB-839 and IACS-6274), resulted in reduced cell viability and clonogenic survival in tumor cells with PI3K/PTEN mutation compared to wild-type. Orthogonal evaluations using glutamine agonists, GLS inhibitors, and mass spectrometric point to a significant role played by PI3K/PTEN mutations in altering cervix tumor cell metabolism towards a more glutamine dependent phenotype. This study suggests a potential strategy for improving the treatment of PI3K-AKT-altered cervical tumors by targeting glutamine and asparagine metabolism in combination with standard therapies. These treatment strategies are currently being evaluated in vivo using a patient derived xenograft model with PIK3CA E545K mutation as well as an immunocompetent cervical tumor model in mice with PTEN deletion."

Cervical Cancer • Oncology • Solid Tumor • PI3K • PIK3CA • PTEN

Metabolites from plasma-like medium fuel nitrogen metabolism and influence proliferation in Leptospira interrogans. (PubMed, bioRxiv) - "A small-molecule inhibitor blocking glutamine utilization, JHU-083, effectively impaired the proliferation of sHPLM cultures...We also discovered that L. interrogans increases its growth rate, upregulates its expression of biosynthetic pathways when exposed to glutamine, and increases its formation of biofilm. Our results reveal the importance of glutamine in supporting the lifecycle of leptospirosis-causing bacteria."

Journal • Infectious Disease

Glutamine antagonist prodrug JHU083 reprograms immune-suppressive tumor-associated macrophages (TAMs) to drive tumor immunity in urologic cancers (AACR 2025) - "There is no abstract associated with this presentation."

Genito-urinary Cancer • Oncology

Nanotherapeutic Macrophage-Neuro Reprogramming Through Immunometabolic Crosstalk Mitigates Sepsis-Induced Lung Injury and Neurologic Damage. (PubMed, Adv Sci (Weinh)) - "Here, we report a rationally engineered, dual-functional, enzyme-responsive nanoplatform (SJNPs) that co-delivers the glutamate production inhibitor JHU083 and the neuroprotective spermine (Spm) to reprogram macrophage-neuron immunometabolic interactions...In murine sepsis models, SJNPs attenuated systemic cytokine storms, mitigated alveolar damage, alleviated neurological injury, and improved survival. This study identifies macrophage-neuron immunometabolic crosstalk as a previously underexplored therapeutic target for septic lung injury characterized by neuronal damage, and establishes metabolic reprogramming of macrophages as a promising strategy for integrated immunomodulatory and neuroprotective therapy in sepsis."

Journal • Critical care • Immune Modulation • Immunology • Infectious Disease • Inflammation • Respiratory Diseases • Septic Shock

HB023: A glutamine antagonist prodrug boosting antitumor lmmunity via PD-L1 suppression and mitochondrial membrane remodeling. (PubMed, J Adv Res) - "HB023 successfully addresses the challenge of glutamine deprivation-induced immune escape by integrating metabolic inhibition with immune checkpoint blockade. This dual-modulatory approach reprograms the tumor immune microenvironment and improves immunotherapeutic efficacy, representing a promising strategy for advancing cancer treatment."

IO biomarker • Journal • Oncology • PD-L1

Positron emission tomography imaging detected enhanced anti-tumor immunity in triple-negative breast cancer mediated by glutamine antagonism (SABCS 2025) - "Our prior study has shown that TNBC tumors are enriched with myeloid-derived suppressor cells (MDSCs), which were significantly reduced by a pan-glutamine metabolic inhibitor JHU083, a pool compound of DRP-104/ Sirpiglenastat being evaluated in clinical trials. By selectively disrupting metabolism in cancer cells and MDSCs while sparing T cells that provide anti-tumor control, glutamine antagonism has immediate translational relevance for adoptive immunotherapies. Although ICI therapy removes PD-1 and CTLA4 mediated inhibition on T cells, it fails to inhibit tumor growth likely due to predominant presence of MDSCs which suppress CD8+ T cells as demonstrated by co-culture data. Combining JHU083 with ICI reduces MDSC infiltration to the tumor, leading to enhanced anti-tumor immunity detected by [89Zr]CD69 PET."

IO biomarker • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD69 • CD8 • GZMB • ITGAM • PTPRC

Glutamine antagonism suppresses tumor growth in adrenocortical carcinoma through inhibition of de novo nucleotide biosynthesis. (PubMed, bioRxiv) - "Treatment with glutamine antagonists 6-Diazo-5-Oxo-L-Norleucine (DON) and JHU-083 elicited robust anti-tumor responses...High expression of Gln-metabolizing genes mediating de novo nucleotide biosynthesis is associated with poor prognosis in ACC. DON drives nucleotide depletion and DNA damage, leading to potent synergy with inhibition of the DNA damage response.Untargeted serum metabolomic analysis in a large cohort of patients with adrenal tumors demonstrates dysregulation of Gln and nucleotide metabolism in ACC."

Journal • Adrenal Cortex Carcinoma • Genito-urinary Cancer • Metabolic Disorders • Oncology • Solid Tumor

Immunometabolic Rewiring of Dendritic Cells to Overcome Glutamine-Driven Immune Suppression in Colorectal Cancer. (PubMed, Adv Sci (Weinh)) - "While glutamine antagonists such as JHU083 inhibit tumor metabolism, they are insufficient to fully restore DC activity...Notably, T26 also demonstrates strong synergy with chemotherapy, immune checkpoint blockade, and anti-angiogenic therapy, significantly improving tumor control without inducing systemic toxicity. These findings position T26 as a mechanistically integrated and translationally promising strategy to overcome glutamine-driven immune suppression and enhance immunotherapy efficacy in CRC and other metabolically dysregulated malignancies."

Journal • Colorectal Cancer • Oncology • Solid Tumor

Suppressing glutamine metabolism in the pancreatic cancer microenvironment can enhance the anti-tumor effect of CD8 T cells and promote the efficacy of immunotherapy. (PubMed, Front Immunol) - "In addition, we found that the glutamine metabolism inhibitor JHU083 promoted the infiltration of CD4 and CD8 T cells and T lymphocyte differentiation, and increased the efficacy of PD-1 inhibitors. Glutamine inhibitors can inhibit the apoptosis of immune cells in the tumor microenvironment, while promoting CD8 T cells activation and cytotoxicity increase. Inhibition of glutamine metabolism within the pancreatic cancer microenvironment results in reduced apoptosis of immune cells, heightened activation and cytotoxicity of CD8 T cells, and a substantial enhancement in the therapeutic efficacy of immunotherapy."

IO biomarker • Journal • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • CD4 • CD8

Modulating Glutamine Metabolism Reprograms Pro-Inflammatory Differentiation in Macrophages. (PubMed, bioRxiv) - "Previous in vivo studies demonstrated that JHU083/DON, a glutamine analog drug, potently reprograms M1/M2 macrophages...In contrast, M2 and tumor-associated macrophages (TAM), which are immunosuppressive, were more susceptible to DON, leading to functional suppression. Collectively, our findings uncover stage-specific mechanisms by which glutamine inhibition modulates M1 polarization, offering a mechanistic rationale for therapeutic strategies that sustain pro-inflammatory, anti-tumor macrophage activity while concurrently suppressing immunosuppressive myeloid subsets in cancer."

Journal • Oncology

The Glutaminase Inhibitor JHU-083 Mitigates Cognitive Dysfunction in a Mouse Model of Post-traumatic Stress Disorder. (PubMed, Neuropharmacology) - "Furthermore, JHU-083 may enhance neurocognitive function and ameliorate hippocampal synaptic deficits in PTSD model mice through the PI3K signaling pathway. These findings suggest that the GLS inhibitor JHU-083 can improve anxiety and cognitive dysfunction in mice exhibiting PTSD-like behaviors, likely by enhancing neuronal repair and synaptic plasticity in the hippocampus via modulation of the PI3K signaling pathway."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Depression • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry

Inhibition of Glutamine Metabolism Attenuates Tumor Progression Through Remodeling of the Macrophage Immune Microenvironment. (PubMed, Adv Biol (Weinh)) - "Ex vivo bone marrow-derived macrophage cultures further confirmed that M2 macrophages were more sensitive to glutamine antagonist than M1 macrophages. Together, our findings indicate that JHU083 exerted its anti-tumor activity not only through direct targeting of glutamine-addicted cancer cells but also by shifting the M1/M2 macrophage landscape in favor of an immune-stimulatory microenvironment."

Journal • Endometrial Cancer • Oncology • Ovarian Cancer • Solid Tumor • MYC

Beyond the tumor: Enhancing pancreatic cancer therapy through glutamine metabolism and innovative drug delivery. (PubMed, J Cell Commun Signal) - "Multiple strategies have emerged to disrupt this dependence: glutamine antagonists (DON and its prodrugs DRP-104, JHU-083), small-molecule glutaminase inhibitors (CB-839), antibody-drug conjugates targeting the ASCT2 transporter, and combination regimens pairing glutamine blockade with immune checkpoint inhibitors. Nanoparticle formulations-including pH-sensitive and PEGylated liposomes co-delivering DON and gemcitabine-enable targeted delivery and reduce off-target toxicity...To overcome these escape routes, future interventions must concurrently target compensatory pathways and integrate biomarker-driven patient selection. Combining glutamine-targeted agents with inhibitors of asparagine synthesis or lipid oxidation, guided by multi-omics profiling, promises a more durable therapeutic benefit and lays the groundwork for personalized treatment of PDAC."

IO biomarker • Journal • Review • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • ASNS • HIF1A • KRAS • MYC • SLC1A5

A novel glutamine metabolism inhibitor improves phagocytic abilities of macrophages by reprogramming glutathione metabolism (IMMUNOLOGY 2025) - "In conclusion, JHU083, a Gln metabolism inhibitor prodrug, alleviates cellular oxidative stress in macrophages, ultimately improving their phagocytic activities and reducing intracellular bacterial burden. Hence, we have identified a new metabolic mechanism that drives the antibacterial activity of JHU083 at least ex-vivo.Keywords: Animals Rodent; Cells Monocytes/Macrophages; Infections Bacterial; Processes Phagocytosis; Tissues Lung"

Infectious Disease • Oncology • Respiratory Diseases • Tuberculosis

Combined inhibition of de novo glutathione and nucleotide biosynthesis is synthetically lethal in glioblastoma. (PubMed, Cell Rep) - "Combining BSO with the glutamine antagonist JHU-083 is synthetically lethal in vitro and in vivo and significantly extends the survival of mice bearing intracranial GBM xenografts. Collectively, our studies advance our understanding of oncogene-induced metabolic vulnerabilities in GBMs."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • TERT

Inhibition of Glutamine Metabolism Suppresses Tumor Progression through Remodeling of the Macrophage Immune Microenvironment. (PubMed, bioRxiv) - "Our findings support a converged mechanism of glutamine metabolism antagonists. JHU083 exerted its anti-tumor efficacy through not only direct targeting of glutamine-addicted cancer cells but also by suppressing glutamine-dependent M2 macrophages, leading to a shift in the M1/M2 macrophage landscape in favor of an immune-stimulatory microenvironment."

Journal • Gynecologic Cancers • Oncology

Gefitinib Reverses PD-L1-Mediated Immunosuppression Induced by long-term Glutamine blockade in Bladder Cancer. (PubMed, Cancer Immunol Res) - "Combination treatment of JHU083 and gefitinib reversed the up-regulation of PD-L1 in bladder cancer cells induced by prolonged glutamine blockade, resulting in the alleviation of T-cell immunosuppression and a significant improvement in therapeutic outcome. These preclinical findings show promise for glutamine metabolism targeting as a viable therapeutic strategy for bladder cancer, with the potential for further enhancement through combined treatment with gefitinib."

IO biomarker • Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • JUN • PD-L1

Metabolic Reprogramming of Tumor-associated Macrophages using Glutamine Antagonist JHU083 Drives Tumor Immunity in MyeloidRich Prostate and Bladder Cancer Tumors (PCF 2024) - No abstract available

Bladder Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Exploiting a critical vulnerability to glutamine antimetabolite therapy in fibrolamellar hepatocellular carcinoma (FLC) (CRI-ENCI-AACR ICIC 2024) - P1/2 | "Our preliminary data using preclinical models of FLC and human biospecimens from FLC patients shows that the DNAJB1-PRKACA fusion results in a metabolic rewiring of the tumor cell characterized by glutamine dependence...Furthermore, the combination of JHU-083, a glutamine antagonist, in combination with checkpoint inhibitor therapy dramatically improved antitumor effects and enhanced survival in a preclinical model of FLC...Patients will receive DRP-104 (145 mg s.c. twice weekly) in combination with a fixed dose of durvalumab (1500 mg i.v. every 28 days)...Secondary objectives include progression free survival (PFS), overall survival (OS), and immunological correlates (NCT06027086). Through this trial, we will test the hypothesis that glutamine antagonism in FLC reverses resistance to immune checkpoint inhibitor (ICI) therapy through modulating the TiME."

CNS Disorders • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Metabolic Disorders • Oncology • Psychiatry • Solid Tumor • DNAJB1 • PRKACA

Glutaminase - A potential target for cancer treatment. (PubMed, Biomedicine (Taipei)) - "Inhibition of glutaminase aggravates oxidative stress by reducing glutathione level, thus leading to apoptotic-mediated cell death in cancer cells Therefore, inhibiting the glutaminase activity using glutaminase inhibitors such as BPTES, DON, JHU-083, CB-839, compound 968, etc. may answer many intriguing questions behind the uncontrolled proliferation of cancer cells and serve as a prophylactic treatment for cancer. Earlier reports neither discuss nor provide perspectives on exact signaling gene or pathway. Hence, the present review highlights the plausible role of glutaminase in cancer and the current therapeutic approaches and clinical trials to target and inhibit glutaminase enzymes for better cancer treatment."

Journal • Review • Oncology • GLS1