telaglenastat (CB-839) / Cornerstone Pharma, Synhale Therapeutics - LARVOL DELTA

Multi-omics reveals immune features in immune and non-immune cells, an IFN-γ/IFN-α-B2M positive feedback loop, and targeted metabolic therapy in multiple myeloma (ASH 2025) - "This multi-omics study delineates the complex cellular architecture of the MM TME, uncovers a novel IFN-γ/IFN-α–B2M positive feedback loop central to immune evasion and disease progression, and identifies CB-839+EGCG as a promising metabolic therapy. Our atlas provides a comprehensive resource for elucidating MM pathogenesis and tailoring targeted immunometabolic interventions."

Immune cell • IO biomarker • Hematological Malignancies • Multiple Myeloma • B2M • BCL2 • CD8 • GLS1 • IFNA1 • IFNG • IL6 • KRAS • LDHA • STAT3

Immunotherapy resistant ALL cells exhibit selective dependence on glutamine and specific transporters for growth and survival (ASH 2025) - "Introduction: Acute lymphoblastic leukemia (ALL) needs newer therapeutic options, especially in patientsthat fail targeted immunotherapies such as CD19 CART and blinatumomab...Treatmentwith the glutaminase inhibitor CB-839 sensitized resistant cells, consistent with their enhanced relianceon glutamine for energy production... CD19 immunotherapy resistant ALL cells exhibit increased expression of both glutaminaseand specific glutamine transporter SLC38A1. Our findings suggest that CD19 immunotherapy resistantcells are dependent on glutamine as a source of cellular energy. Further, our data suggests thatglutamine is selectively utilized for cellular energy in resistant cells, while it is shunted toward additionalpathways in parental cells, including the formation of asparagine and glutathione."

IO biomarker • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • CD19 • CD22

TEPH: Telaglenastat Efficacy in Pulmonary Hypertension (clinicaltrials.gov) - P1/2 | N=28 | Not yet recruiting | Sponsor: Chan, Stephen, MD, PhD | Initiation date: Nov 2025 ➔ Feb 2026 | Trial primary completion date: Sep 2027 ➔ Sep 2028

Trial initiation date • Trial primary completion date • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Glutamine Promotes Myogenesis in Myoblasts Through Glutaminolysis-Mediated Histone H3 Acetylation That Enhances Myogenin Transcription. (PubMed, Nutrients) - " Glutamine, glutamate, and DM-α-KG promoted C2C12 myoblast differentiation in a concentration-dependent manner, whereas the glutaminase inhibitor CB-839 suppressed differentiation... This report demonstrates glutaminolysis-dependent histone H3 acetylation, which induces myogenin transcription in myoblasts. These results, connecting glutamine supplementation during resistance training, may make it an effective strategy to accelerate muscle regeneration."

Journal • Myogenin

Integrating biochemical and computational approaches to identify targeted therapeutic strategies for liver fibrosis: Effects of Telaglenastat (CB-839) on the glutaminase pathway. (PubMed, Biochem Biophys Res Commun) - "These findings demonstrate that CB-839 exhibits significant antifibrotic effects in a rat model of liver fibrosis, primarily by modulating glutamine metabolism and key fibrotic biomarkers. CB-839 has the potential to be a promising therapeutic approach for liver fibrosis."

Journal • Fibrosis • Gastroenterology • Hepatocellular Cancer • Hepatology • Immunology • Liver Cirrhosis • Oncology • Solid Tumor • MMP2 • PPARA • PPARG • TGFB1 • TIMP1

Macropinocytosis and Vascularization Determine Response to mTOR Inhibitors in Lung Squamous Cell Carcinoma. (PubMed, Cancer Res) - "Moreover, prolonged treatment of LUSC PDXs with TAK228 and the glutaminase inhibitor CB-839 led to upregulation of vascularization, which coincided with a rebound in tumor growth despite continued therapeutic administration. These findings highlight adaptive resistance mechanisms to small molecule inhibitors that target key metabolic pathways, lending insight into potential future clinical strategies for the treatment of LUSC."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma

Niosomal co-delivery of metformin and telaglenastat: A targeted nanotherapeutic strategy for breast cancer treatment and metastasis suppression in 2D and 3D models. (PubMed, Biomed Pharmacother) - "In conclusion, coordinated inhibition of GLUT-1- and GLS-1-driven metabolism via MET/TEL-loaded niosomes achieves enhanced cytotoxicity, durable spheroid penetration, and strong anti-migratory and metabolic modulatory effects. This stable co-delivery platform represents a promising nanotherapeutic strategy to overcome metabolic adaptability and treatment resistance in breast cancer."

Journal • Breast Cancer • Oncology • Solid Tumor • SLC2A1

Stroma-driven horizontal transfer of TCA-related proteins mediates metabolic plasticity and imatinib resistance in chronic myeloid leukemia. (PubMed, Cell Commun Signal) - "This study describes a novel mechanism of direct bone marrow-mediated protection of leukemic cells from imatinib/TKI, related to transfer of metabolic proteins leading to higher activity of TCA cycle, metabolic plasticity and adaptation. Targeting the stroma-driven TCA cycle-related metabolism combined with imatinib presents a promising strategy to achieve therapeutic efficacy to overcome bone marrow microenvironment-mediated protection in CML."

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • CD34

Structure-enabled discovery of carboxylate esters prodrugs as potential potent inhibitors targeting Glutaminase C. (PubMed, Bioorg Chem) - "Herein, a series of acidic derivatives targeting the basic hotspot were designed based on the scaffold of CB839...Prodrug 16 showed pronounced antiproliferative activity in A549 cells (IC50 = 2.45 nM) alongside favorable stability, and additionally regulated cellular metabolites and increased reactive oxygen species by blocking glutamine metabolism. Ultimately, prodrug 16 exhibits strong in vivo antitumor activity in an A549 xenograft model, establishing it as a highly potent GAC inhibitor and suggesting a novel approach for the development of next-generation GAC-targeting therapeutics."

Journal • Oncology

Targeting METTL3 Induces a Metabolic Vulnerability in ER+ Breast Carcinoma Cells. (PubMed, Endocr Relat Cancer) - "CB-839 increased the potency of STM2457 only in the LCC9 and ZR-75-1-4-OHT endocrine-resistant cells. Our collective findings suggest that METTL3 inhibition leads to selective glycolytic and oxidative metabolic changes between these endocrine-sensitive and resistant BC cells that can be exploited for combinatorial therapy."

Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • GLS1 • HK2 • METTL3 • SLC1A5

Testing of the Anti Cancer Drugs CB-839 HCl (Telaglenastat) and MLN0128 (Sapanisertib) in Advanced Stage Non-small Cell Lung Cancer (clinicaltrials.gov) - P1 | N=22 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | N=85 ➔ 22 | Trial completion date: Jun 2026 ➔ Nov 2026 | Trial primary completion date: Jun 2026 ➔ Nov 2025

Enrollment change • Trial completion date • Trial primary completion date • Brain Cancer • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BRAF • KEAP1 • KRAS • NFE2L2 • ROS1

Metabolic nanoblockers for synergistic cancer treatment through glutaminase inhibition and sonodynamic therapy. (PubMed, Ultrason Sonochem) - "To address these challenges, we herein developed metabolic nanoblockers (CBE@AM NPs) by encapsulating a glutamine metabolism inhibitor CB839 and a sonosensitizer chlorin e6 (Ce6) into melanin-inspired nanoparticles...Concurrently, they inhibited the glutamine metabolism in the tumor, disrupting redox homeostasis and remodeling the immunosuppressive TME, thereby amplifying both SDT-generated oxidative stress and ICD-induced antitumor immunity. CBE@AM NPs demonstrated a potent tumor-inhibitory effect in tumor-bearing mice, highlighting their potential for immunometabolic reprogramming to enhance the therapeutic efficacy of SDT."

Journal • Oncology

Immune suppression in MTAP-deficient cancers via glutamate metabolism and CXCL10 downregulation. (PubMed, Front Immunol) - "Several glutamate pathway inhibitors, including the clinically tested glutaminase inhibitor CB-839, selectively impaired their growth...These findings uncover a novel link between glutamate metabolism and immune modulation in MTAP-deficient tumors. Our study provides mechanistic and preclinical support for targeting glutamate pathways to both suppress tumor growth and convert immune-cold tumors into more immunoresponsive states, offering a promising strategy to enhance ICI efficacy in this challenging cancer subtype."

IO biomarker • Journal • Immune Modulation • Immunology • Oncology • CXCL10 • MTAP • PTPRC

Targeting Glutamine Dependence through GLS1 Inhibition Suppress Multiple Myeloma and Phenomenon of Sars-Cov-2 Infectious Disease (ASH 2023) - "Combined treatment with panobinostat and telaglenastat caused more cytotoxicity. The GLS is involved myeloma progress and GLS inhibitor suppresses myeloma cells and enhance cytotoxic effects of HDAC inhibitor. We also provide the GLS inhibitor is effective to SARS-CoV-2 phenomenon and promising clinical relevance as a candidate drug for treatment of myeloma patients in COVID-19 pandemic."

Hematological Malignancies • Infectious Disease • Monoclonal Gammopathy • Multiple Myeloma • Oncology • Respiratory Diseases • CASP3 • CASP7 • GLS1 • TNFA

Rational Design of Non-Toxic Multidrug Combinations Demonstrates Durable and Hypoxia-Enhanced Efficacy Against Renal Cell Carcinoma. (PubMed, Pharmaceutics) - " From an initial panel of 10 drugs, either approved or undergoing clinical trial, the optimized drug combinations (ODCs) contained crizotinib, telaglenastat, U-104, and vismodegib at clinical and subtherapeutic doses. Moreover, chronic exposure of 786O and UOK276 cells led to durable responses, suggesting a prolonged effect in responders. Our findings demonstrate the potential of optimized, non-toxic drug combinations as a highly selective and effective strategy for accelerating the development of precision RCC treatment."

Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Sarcoma • Solid Tumor

Biomimetic nanoplatform-mediated CRISPR/Cas9 delivery for dual-pathway metabolic blockade in head and neck squamous cell carcinoma. (PubMed, Biomaterials) - "Head and neck squamous cell carcinoma (HNSCC) continues to exhibit a poor prognosis, largely due to late diagnosis and the development of cisplatin resistance...This nanoplatform enables coordinated co-delivery of telaglenastat (a glutaminase 1 (GLS1) inhibitor) and a CRISPR-Cas9 plasmid encoding sgRNA targeting HIF-1α...Notably, in vivo studies showed a 90 % tumor inhibition rate (TIR) after 15 days of treatment, through enhanced apoptosis, reduced proliferation, and tumor glucose/glutamate depletion. Collectively, P-T-p@CM establishes a paradigm-shifting approach to disrupt metabolic compensation in the treatment of HNSCC."

Journal • Head and Neck Cancer • Metabolic Disorders • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • HIF1A

Developing a Therapeutic Strategy for Targeting Metabolic Vulnerability of TET2 Mutant Leukemia (ASH 2024) - "Given that the TET2 inhibitors Eltrombopag (Epag) and TETi76 mimic the loss of TET2 and create similar disruptions in glutaminolysis, a combination therapy approach for non-TET2 mutated AML using TETi and CB839 can be utilized. This discovery paves the way for a biomarker-driven, novel therapeutic strategy for myeloid leukemia. Furthermore, our research highlights the potential of combining TET2 inhibitors with glutaminolysis inhibitors as a pioneering treatment approach for a broad range of leukemia types."

Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • CNS Disorders • Hematological Malignancies • Leukemia • Metabolic Disorders • Myelodysplastic Syndrome • Oncology • Psychiatry • GLI2 • TET2

GLS1 inhibitor CB-839 inhibits the malignant progression of 5-FU resistant hepatoma cells by regulating glutamine metabolism. (PubMed, Chem Biol Interact) - "As a first-line chemotherapeutic agent for HCC, 5-fluorouracil (5-FU) has demonstrated significant efficacy in suppressing tumor cell proliferation through its cytotoxic mechanisms. Specifically, they may suggest targeting glutamine metabolism as a potential avenue for intervention and offer novel perspectives on understanding this resistance. Concurrently, these discoveries provide some support for optimizing chemotherapy regimens, with the aim of surmounting the current clinical challenges in reversing drug resistance."

Journal • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor

Biomimetic Organic Nanozyme as Tumor Vaccines for Targeted Suppression of Ammonia-Induced T Lymphocyte Death to Augment Breast Cancer Immunotherapy. (PubMed, Adv Sci (Weinh)) - "Furthermore, the released CB-839 reduces intracellular ammonia levels in T cells, thereby enhancing anti-tumor immunity. This pioneering work achieves targeted AITD inhibition for the first time, integrating NIR-PDT, metabolic modulation, and immune activation to advance nanozyme-based immunotherapy."

Journal • Breast Cancer • Oncology • Solid Tumor • CD8

Glutaminase inhibitor CB-839 causes metabolic adjustments in colorectal cancer cells (Nature) - "CB-839 treatment altered cell cycle progression and increased glycolytic ATP production in HT29 cells. Metabolomic analysis revealed changes in Krebs cycle and glutaminolysis in both cell lines, along with alterations in amino acids, sugars, antioxidants, and organic acid levels."

Preclinical • Colorectal Cancer

TEPH: Telaglenastat Efficacy in Pulmonary Hypertension (clinicaltrials.gov) - P1/2 | N=28 | Not yet recruiting | Sponsor: Chan, Stephen, MD, PhD

New P1/2 trial • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Glutaminase inhibitor CB-839 causes metabolic adjustments in colorectal cancer cells. (PubMed, Sci Rep) - "Metabolomic analysis revealed changes in Krebs cycle and glutaminolysis in both cell lines, along with alterations in amino acids, sugars, antioxidants, and organic acid levels. This study highlighted glutamine's key role in CRC cells and provided a foundation for elucidating the mechanisms of response and resistance to CB-839."

Journal • Colorectal Cancer • Oncology • Solid Tumor

Targeting glutamine catabolism suppresses eosinophil expansion and activation to alleviate allergic airway inflammation. (PubMed, Biochem Pharmacol) - "In contrast, CB839 significantly decreased eosinophil infiltration, tissue pathology, and inflammatory cytokine expression in vivo. Together, these findings uncover an essential role for glutamine metabolism in eosinophil biology and identify GLS1 inhibition by CB839 as a promising therapeutic strategy for eosinophilic asthma."

Journal • Asthma • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases

BEGIN: A Basket Trial of Glutaminase inhibition with Telaglenastat in NF1, KEAP1/NRF2, and STK11/LKB1-Altered Tumors (AACR-NCI-EORTC 2025) - P2 | "While the clinical development of the agent was discontinued, these findings demonstrate preliminary clinical activity of GLS inhibition in NF1-mutant melanoma and MPNST, providing proof-of-concept and supporting further investigation with biomarker-driven combination strategies."

IO biomarker • Late-breaking abstract • Pan tumor • Brain Cancer • Melanoma • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor • KEAP1 • NF1 • NFE2L2 • STK11

Glutaminase Reprogramming in Hepatocellular Carcinoma: Implications for Diagnosis, Prognosis, and Potential as a Novel Therapeutic Target. (PubMed, Int J Mol Sci) - "Inhibiting GLS1 with CB-839 significantly impacted glutamine metabolism in HCC cells while showing limited activity on normal hepatocytes...Overexpressed GLS1 and loss of GLS2 within tumors convey an unfavorable prognosis in patients with HCC. Pharmacological inhibition of GLS1 in HCC cells successfully harnesses glutamine metabolism, representing an attractive target for novel therapeutic approaches."

Journal • Fibrosis • Hepatocellular Cancer • Hepatology • Immunology • Liver Cancer • Oncology • Solid Tumor • GLS1 • GLS2