JHU083 / Johns Hopkins University, AstraZeneca - LARVOL DELTA

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

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

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

Identification of glutamine metabolism as a druggable therapeutic vulnerability for adrenocortical carcinoma (ENDO 2024) - "Treatment with the L-DON pro-drug JHU-083, in vivo, led to marked growth inhibition of subcutaneous mouse ACC tumor implants in both immunocompetent and immunodeficient mice...Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO."

Adrenal Cortex Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • CTNNB1

T Cell Metabolic Reprogramming by Glutamine Blockade Reduces Kidney Fibrosis after Severe Ischemia-Reperfusion Injury (ATC 2024) - "Reconstitution of T cell metabolism by glutamine antagonism after severe IRI reduced kidney fibrosis, increased kidney DN T cells, and decreased effector CD4+ T cell activation. This novel approach could improve short- & long-term outcomes after severe DGF."

Cardiovascular • Fibrosis • Immunology • Reperfusion Injury • CD4 • CD69 • CD8 • CPT1A • mTOR • VDAC1

Metabolic reprogramming of tumor-associated macrophages using glutamine antagonist JHU083 drives tumor immunity in myeloid-rich prostate and bladder cancer tumors. (PubMed, Cancer Immunol Res) - "Although the anti-tumor effect of glutamine antagonism on tumor-infiltrating T cells was moderate, JHU083 promoted a stem cell-like phenotype in CD8+ T cells and decreased Treg abundance. Finally, JHU083 caused a ubiquitous shutdown in glutamine utilizing metabolic pathways in tumor cells, leading to reduced HIF-1alpha, c-MYC phosphorylation, and induction of tumor cell apoptosis, all key anti-tumor features."

Journal • Bladder Cancer • Genito-urinary Cancer • Metabolic Disorders • Oncology • Solid Tumor • Urology • CD8 • HIF1A • MYC

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

A redox-responsive prodrug for tumor-targeted glutamine restriction. (PubMed, J Control Release) - "When applied to treat mice bearing subcutaneous CT26 mouse colon carcinoma, redox-DON exhibited equivalent antitumor efficacy but a greatly improved safety profile, particularly, in spleen and gastrointestinal tract, as compared to the state-of-the-art DON prodrug, JHU083...Our results suggest that redox-DON is a safe and effective therapeutic for tumor-targeted glutamine inhibition showing promise for enhanced metabolic modulatory immunotherapy. The approach of reversible chemical modification may be generalized to other metabolic modulatory drugs that suffer from overt toxicity."

Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Disorder • Immune Modulation • Immunology • Oncology • Solid Tumor

Targeting glutamine metabolism exhibits anti-tumor effects in thyroid cancer. (PubMed, J Endocrinol Invest) - "Thyroid cancer exhibited enhanced glutamine metabolism, as evidenced by the glutamine dependence of thyroid cancer cells and high expression of multiple glutamine metabolism-related genes. Targeting glutamine metabolism with DON prodrug could be a promising therapeutic option for advanced thyroid cancer."

Journal • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • CCNA2 • CDH2 • CDK2 • GLS1 • MMP2 • MMP9 • PD-L1 • VIM

Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities against Mycobacterium tuberculosis. (PubMed, Nat Commun) - "JHU083 treatment also initiates earlier T-cell recruitment, increased proinflammatory myeloid cell infiltration, and a reduced frequency of immunosuppressive myeloid cells when compared to uninfected and rifampin-treated controls. When tested in an immunocompromised mouse model of Mtb infection, JHU083 loses its therapeutic efficacy suggesting the drug's host-directed effects are likely to be predominant. Collectively, these data reveal that JHU083-mediated glutamine metabolism inhibition results in dual antibacterial and host-directed activity against tuberculosis."

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

Leveraging metabolic vulnerabilities induced by TERT expression for glioblastoma therapy in vivo. (SNO 2023) - "This effect is specific to TERT-expressing GBM cells because the combination of DON and BSO does not affect viability of normal astrocytes or astrocytomas that use the ALT pathway for telomere maintenance. Importantly, in vivo stable isotope tracing confirmed that combined treatment with JHU-083 (a brain-penetrant prodrug of DON) and BSO abrogates synthesis of GSH, aspartate, and pyrimidine nucleotides from [U-13C]-glutamine and induces apoptotic death in mice bearing intracranial GBM6 tumors.Collectively, our studies highlight the therapeutic potential of targeting metabolic vulnerabilities induced by TERT expression in GBMs in vivo."

Preclinical • Astrocytoma • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • TERT

Glutamine blockade and anti-PD1 treatment reprograms the tumor infiltrating myeloid cells in mouse model of soft tissue sarcomas (SITC 2023) - "3 We used JHU083, a novel prodrug of a glutamine antagonist (6-Diazo-5-oxo-L-norleucine) to rid the TME of glutamine and interrogate its downstream effects on the TIME...Transcriptional changes upon glutamine blockade, especially upregulation of Apoe, a key apolipoprotein implicated in cholesterol transport points towards rewiring of metabolism of the myeloid cells. This hints that the heterogenous metabolome/lipidome might hold clues to the differential responses to glutamine blockade in the myeloid subsets."

IO biomarker • Preclinical • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • APOE • C1QA • C1QB • CALR • CSF3 • CSF3R • KRAS

Glutamine Blockade After Severe AKI Reduces Kidney Fibrosis by T-Cell Metabolic Reprogramming (KIDNEY WEEK 2023) - "Reconstitution of T cell metabolism by glutamine blockade after severe AKI reduced kidney fibrosis, increased kidney DN T cells and decreased effector CD4 T cell activation. This is a novel approach to potentially mitigating AKI to CKD, as well as other causes of CKD progression."

Cardiovascular • Fibrosis • Immunology • CD4 • CD69 • CD8 • CPT1A • mTOR • VDAC1

DNAJB1-PRKACA fusion in fibrolamellar hepatocellular carcinoma induces glutamine addiction and an immunosuppressive tumor microenvironment (AACR 2023) - "Fibrolamellar hepatocellular carcinoma (FLC) is a rare and often lethal form of liver cancer that primarily affects children and young adults. Systemic treatment of BALB/c mice bearing TIBx-FLC tumors with JHU-083, a glutamine antagonist, in combination with immune checkpoint inhibitor therapy enhanced survival as compared to vehicle or monotherapy. These data identify altered glutamine metabolism as a target in FLC, and may provide an explanation for immune suppression seen in the FLC tumor microenvironment."

Biomarker • Tumor microenvironment • Gastrointestinal Cancer • Hepatoblastoma • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • CD8 • DNAJB1 • PRKACA

T cell metabolic reprogramming in acute kidney injury and protection by glutamine blockade. (PubMed, JCI Insight) - "Given a convergent role for glutamine in T cell metabolic pathways and the availability of a relatively safe glutamine antagonist JHU083, effects on AKI were evaluated...In vitro hypoxia demonstrated upregulation of glycolysis-related enzymes. T cells undergo metabolic reprogramming during AKI, and reconstitution of metabolism by targeting T cell glutamine pathway could be a promising novel therapeutic approach."

Journal • Acute Kidney Injury • Nephrology • Renal Disease • CPT1A • mTOR • SLC2A1

H1N1 influenza virus infection through NRF2-KEAP1-GCLC pathway induces ferroptosis in nasal mucosal epithelial cells. (PubMed, Free Radic Biol Med) - "In addition, A glutaminase antagonist, JHU-083, also demonstrated that glutaminolysis can regulate the NRF2-KEAP1-GCLC signal pathway and ferroptosis. According to this study, H1N1 virus can induce the ferroptosis of hNECs via the NRF2-KEAP1-GCLC signal pathway and glutaminolysis, leading to nasal mucosal epithelial inflammation. This discovery is expected to provide an attractive therapeutic target for viral-induced nasal inflammation."

Journal • Infectious Disease • Inflammation • Influenza • Respiratory Diseases

ZFTA-RELA fusion aberrantly drives glutamine metabolism in lethal pediatric ependymomas (AACR 2023) - "Moreover, JHU-083, a specific pharmacologic inhibitor of glutaminase, killed ZFTA-RELAFUS tumor cells in vitro and in vivo. To summarize, our results suggest that the ZFTA-RELA fusion expressing tumor cells exhibit strong glutamine dependence, and targeting it has significant therapeutic relevance."

Clinical • Brain Cancer • Ependymoma • Oncology • Solid Tumor • NF-κβ • RELA • SLC1A5 • ZFTA

Glutamine antagonist prodrug JHU083 reprograms immunosuppressive tumor-associated macrophages (TAMs) to drive tumor immunity in urologic cancers (AACR 2023) - "We found that JHU083 reprograms TAMs from an immunosuppressive to an inflammatory state which we show has a direct anti-tumor effect. These macrophages convert to a highly proliferative and glycolytic state, have increased TNF production which might be resulting in improved phagocytic activity against tumor cells. As urologic cancers are heavily infiltrated with immunosuppressive TAMs, JHU083 is an excellent preclinical candidate."

Bladder Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Urothelial Cancer • CD4 • CD8 • SLC2A1

In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma. (PubMed, Sci Adv) - "Infusions with [amide-N]glutamine revealed persistent amidotransferase activity during glutaminase inhibition, and blocking these activities with the amidotransferase inhibitor JHU-083 also reduced tumor growth in both immunocompromised and immunocompetent mice. We conclude that ccRCC tumorgrafts catabolize glutamine via multiple pathways, perhaps explaining why it has been challenging to achieve therapeutic responses in patients by inhibiting glutaminase."

Journal • Preclinical • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • IDH1 • VHL