AZD-3965 / Cancer Research UK - LARVOL DELTA

Role of monocarboxylate transporters in cancer immunology and their therapeutic potential. (PubMed, Br J Pharmacol) - "Combinational therapy using MCT1 inhibitors (e.g. AZD3965), MCT4 inhibitors and immune checkpoint blockade can suppress lactate-mediated immunosuppression in the TME. By disrupting lactate shuttling between glycolytic and oxidative tumour cells, this strategy promotes T cell function and improves cancer treatment outcomes."

IO biomarker • Journal • Review • Oncology • SLC16A1

Jing An decoction alleviates neuroinflammation in Tourette syndrome by regulating butyrate-mediated microbiota-gut-brain axis. (PubMed, Phytomedicine) - "JA alleviates TS by regulating the GBA axis through butyrate-producing bacteria. Butyrate alleviates neuroinflammation by inhibiting the TLR4/HDAC3/NF-κB pathway, thereby promoting M2 microglial polarization."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Developmental Disorders • Inflammation • Movement Disorders • Psychiatry • Tourette Syndrome • HDAC3

Mitochondrial fission factor drives an actionable metabolic vulnerability in multiple myeloma. (PubMed, Haematologica) - "Finally, we highlight a novel lactate-MFF axis involved in proteasome inhibitor resistance, and show that combining AZD3965 or Syrosingopine with bortezomib results in synergistic anti-MM activity along with MFF down-regulation. Collectively, these data point to MFF-dependent mitochondrial fragmentation as a key metabolic hallmark of MM, providing a framework for the development of novel therapeutic strategies targeting mitochondrial dynamics and harnessing the metabolic plasticity of malignant plasma cells."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology

Lactate induces oxidative phosphorylation in osteoblasts via Gpr81-Stat3 signaling. (PubMed, Cell Signal) - "Inhibition of Gpr81 by 3-OBA or decrease in Gpr81 expression by Gpr81 siRNA, but not the interruption of MCT1 by AZD3965, led to the inhibition of the Gpr81-Jak2-Stat3-Y705 and Gpr81-Akt-Stat3-S727 signaling, and OXPHOS and cell differentiation of MC3T3-E1 cells were also inhibited...Lastly, osteoblast GPR81-deficient mice showed lower bone formation. Thus, these findings propose a novel signaling mechanism by which lactate regulates cell differentiation as well as OXPHOS through the activation of Stat3 signaling by Gpr81."

Journal

Lactate facilitates pancreatic repair following acute pancreatitis by promoting reparative macrophage polarization. (PubMed, Cell Mol Gastroenterol Hepatol) - "Lactate facilitates pancreatic repair by promoting reparative macrophage polarization, achieved through promoting lactylation and inhibiting JAK2-STAT1 signaling. This phenotypic shift alleviates inflammation and facilitates tissue recovery, highlighting a potential therapeutic approach for AP."

Journal • Inflammation • Pancreatitis • GPR132 • PFKFB3

Gastric cancer cells shuttle lactate to induce inflammatory CAF-like phenotype and function in bone marrow-derived mesenchymal stem cells. (PubMed, Mol Immunol) - "Herein, exogenous lactate induced a pro-tumorigenic phenotype in BM-MSCs, which was blocked by AZD3965...Collectively, gastric cancer cells induce an iCAF-like phenotype and function in BM-MSCs through a lactate shuttle mechanism, emphasizing the role of metabolic reprogramming in cellular communication that fosters a supportive tumor microenvironment. Targeting lactate-related pathways may provide new therapeutic strategies to hinder BM-MSCs' supportive roles in gastric cancer."

Journal • Gastric Cancer • Hematological Malignancies • Oncology • Solid Tumor • CAFs • CD8 • CXCL8 • PD-L1 • TGFB1

Tumor cell oxidative metabolism triggers immune escape in advanced kidney cancer (IMMUNOLOGY 2025) - "Furthermore, treating mice with an MCT1 inhibitor (AZD3965) rescued responsiveness to anti-PD-L1 therapy, identifying a novel clinical axis to bolster cancer treatments. In conclusion, this study uncovers a previously underappreciated role for cancer-oxidative metabolism in driving immune evasion and disease progression, identifies its underlying biological mechanisms, and proposes MCT1 inhibition as a promising therapeutic avenue for high risk ccRCC patients.Keywords: Animals Human Rodent; Cells T Cells; Processes Cell Differentiation Cytotoxicity"

Metastases • Tumor cell • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CD8

LACTATE FACILITATES PANCREATIC REPAIR FOLLOWING ACUTE PANCREATITIS BY PROMOTING REPARATIVE MACROPHAGE POLARIZATION (DDW 2025) - "Treatment with AZD3965, a chemical inhibitor of lactate transportation, blocked the effects on lactylation and gene expression... Lactate facilitates pancreatic repair by promoting reparative macrophage polarization, achieved through promoting lactylation and inhibiting JAK2-STAT1 signaling via GPR132. This phenotypic shift alleviates inflammation and facilitates tissue recovery, highlighting a potential therapeutic approach for AP. Keywords : lactate; acute pancreatitis; pancreatic repair; macrophage; lactylation"

Inflammation • Pancreatitis • GPR132 • HMGB1 • LDHA • LRG1 • PFKFB3

Cr (VI) induces lactate utilization through HIF-1α/MCT1 dependent on p53 protein level. (PubMed, Food Chem Toxicol) - "CoCl2, an HIF-1α inducer, increased MCT1, while the HIF-1α inhibitor YC-1 and MCT1 inhibitor AZD3965 suppressed Cr (VI)-induced lactate utilization and cell growth...These findings highlighted the role of p53 protein level in the effects of Cr (VI) on HIF-1α/MCT1 to induce lactate utilization and cell growth. Targeting the p53/HIF-1α/MCT1 pathway could inhibit Cr (VI)-mediated tumorigenesis."

Journal • Oncology • HIF1A • SLC16A1

Impact of MCT1 inhibition on NSCLC metabolism and sensitivity to therapy (AACR 2025) - "AZD3965 did not confer additional cytotoxic effect to cells treated with paclitaxel. MCT1 inhibition decreases lactate import and oxidation in vitro and causes DNA damage to enhance the cytotoxic effects of pemetrexed. MCT1 inhibition decreases lactate import and oxidation in vitro and causes DNA damage to enhance the cytotoxic effects of pemetrexed. Metabolic reprogramming in NSCLC leads to the use of alternate carbon sources, such as lactate, and this can be modeled in both standard and physiologic culture conditions. Notably, this does not appear to be a general sensitization to cell death."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ANXA5 • SLC16A1

Lactic acid inhibits the interaction between PD-L1 protein and PD-L1 antibody in the PD-1/PD-L1 blockade therapy-resistant tumor. (PubMed, Mol Ther) - "Furthermore, we showed that the combination therapy of targeting PD-L1 with our PD-L1 antibody-drug conjugate (PD-L1-ADC) and reducing lactic acid with the monocarboxylate transporter 1 (MCT-1) inhibitor, AZD3965, can effectively treat the PD-1/PD-L1 blockade-resistant tumors. The findings of this study provide a new mechanism of how lactic acid induces an immunosuppressive tumor microenvironment and suggest a potential combination treatment to overcome the tumor resistance to PD-1/PD-L1 blockade therapy."

Journal • Oncology • SLC16A1

The role of tumor microenvironment lactic acid in the cancer cell resistance to anti-PD-L1 and anti-PD-1 blockade therapy (AACR 2025) - "Furthermore, we showed that the combination therapy of targeting PD-L1 with our PD-L1 antibody-drug conjugate (PD-L1-ADC) and reducing lactic acid with the MCT-1 inhibitor, AZD3965, can effectively treat the PD-1/PD-L1 blockade resistant tumors. Altogether, the findings in this study uncover a new mechanism of how lactic acid induces an immunosuppressive tumor microenvironment and suggest a potential combination treatment strategy to overcome the tumor resistance to PD-1/PD-L1 blockade therapy and improve clinical outcomes."

Biomarker • Tumor microenvironment • Oncology

MCT1 regulates the progression of early invasive oral squamous cell carcinoma (AACR 2025) - "An MCT1 inhibitor, AZD3965, was used to assess invasion in OTCs and disease progression in a mouse model of oral carcinogenesis...Our data also suggest potential metabolic vulnerabilities in oral cancer cells can be exploited by targeting cholesterol and lipid synthesis pathways in combination with MCT1 inhibition. Our ongoing work involves further assessment of mechanisms regulated by MCT1 to promote progression of oral cancer, including ATAC-seq to assess epigenetic changes, metabolite analysis and metabolic tracing, and the development of relevant mouse models."

Late-breaking abstract • Oncology • Oral Cancer • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • SLC16A1

Glyceraldehyde-3-Phosphate Dehydrogenase/1,3-Bisphosphoglycerate-NADH as Key Determinants in Controlling Human Retinal Endothelial Cellular Functions: Insights from Glycolytic Screening. (PubMed, J Biol Chem) - "Pharmacological inhibitors targeting lower glycolytic components were tested: heptelidic acid for glyceraldehyde-3-phosphate dehydrogenase (GAPDH), NG-52 for phosphoglycerate kinase (PGK), shikonin for pyruvate kinase M (PKM), galloflavin for lactate dehydrogenase (LDH), AZD3965 for lactate transporter (MCT-1), and MSDC-0160 for the mitochondrial pyruvate carrier (MPC)...GAPDH and its downstream products (1,3-BPG and NADH) are shown to play a pivotal role in maintaining barrier integrity and promoting HREC adhesion and spreading. These findings guide the development of targeted interventions that modulate HREC bioenergetics to treat endothelial dysfunction in various retinal disorders, while minimizing potential adverse effects on healthy endothelial cells."

Journal • Diabetic Retinopathy • Ophthalmology • Retinal Disorders • GAPDH • PKM

Lactate dehydrogenase B deficiency-dependent hyperlactatemia coordinates with necroptosis to worsen septic liver and kidney injuries. (PubMed, Biochem Biophys Res Commun) - "Blockade of necroptosis significantly protects Ldhb-/- mice against septic liver and kidney injuries, enabling a compensation towards the therapeutic efficacy of AZD3965. Our study together unearth the coordination of hyperlactatemia and necroptosis in septic liver and kidney injuries in the context of LDHB deficiency, and support further investigation of combined targeting SLC16A1 and necroptosis for clinical treatment of sepsis with low LDHB activity."

Journal • Hypotension • Infectious Disease • Metabolic Disorders • Septic Shock • LDHB • SLC16A1

A375 melanoma-derived lactate controls A375 melanoma phenotypes by inducing macrophage M2 polarization via TCA cycle and TGF-β signaling. (PubMed, PeerJ) - "Elevated lactate level in PIG1-conditioned medium (PIG1-CM) induced M2 polarization, whereas the lactate transport inhibitor AZD3965 suppressed this effect in PBMCs cultured with A375-CM...Significantly, polarized macrophages altered melanoma phenotypes including proliferation, clone formation, cell cycle, apoptosis, migration and invasion via TCA cycle and TGF-β. Our data collectively demonstrate that lactate derived from melanoma facilitates polarization of M2 macrophages, which subsequently leads to modifications in melanoma phenotypes via TCA cycle and TGF-β signaling."

Journal • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • CD68 • MRC1 • TGFB1 • TNFA

2-[18F]Fluoropropionic Acid PET Imaging of Doxorubicin-Induced Cardiotoxicity. (PubMed, Mol Imaging Biol) - "[18F]FPA, especially when co-administered with AZD3965, is a new tool for imaging changes in fatty acid metabolism occurring in response to doxorubicin-induced cardiomyopathy by PET."

Journal • Cardiomyopathy • Cardiovascular • Metabolic Disorders • Oncology • Pediatrics • SLC16A1

Lactate accumulation promotes immunosuppression and fibrotic transformation of bone marrow microenvironment in myelofibrosis. (PubMed, J Transl Med) - "In conclusion, our results unveil lactate as a key regulator of immune escape and BM fibrotic transformation in MF patients, suggesting MCT1 blocking as a novel antifibrotic strategy."

Journal • Fibrosis • Hematological Disorders • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • SLC16A1

2-[18F]Fluoropropionic Acid PET Imaging of Doxorubicin-induced Cardiotoxicity. (PubMed, Res Sq) - "Co-administration of [ 18 F]FPA and AZD3965 enhanced the imaging contrast of the diseased heart while reducing overall exposure to radioactivity. Conclusions [ 18 F]FPA, especially when co-administered with AZD3965, is a new tool for imaging changes in fatty acid metabolism occurring in response to doxorubicin-induced cardiomyopathy by PET."

Journal • Cardiomyopathy • Cardiovascular • Metabolic Disorders • Oncology • Pediatrics • SLC16A1

Emodin regulated lactate metabolism by inhibiting MCT1 to delay non-small cell lung cancer progression. (PubMed, Hum Cell) - "In vivo experiments had shown that emodin and AZD3965 could effectively inhibit the growth of lung cancer and inhibit the expression of MCT1. All in all, our data suggested that emodin inhibited the proliferation, migration, and invasion of lung cancer cells, possibly by inhibiting MCT1, providing important theoretical basis for elucidating the mechanism of emodin in treating lung cancer."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Transplantation • SLC16A1

Transcriptome analysis of anaerobic glycolysis effects on Jurkat T cell proliferation. (PubMed, Cent Eur J Immunol) - "The monocarboxylate transporter 1 inhibitor AZD3965 was used to target and block the transmembrane transport of lactate, thereby inhibiting anaerobic glycolysis in Jurkat T cells...Anaerobic glycolysis contributes to the regulation of Jurkat T-cell proliferation. The underlying mechanism may involve the estrogen signaling pathway or PI3K-Akt signaling pathway as well as protein metabolism."

Journal • SLC16A1

Development of [18F]-labelled lactate for oxidative cancer imaging (EANM 2024) - "Whole body mouse PET imaging was performed using a Mosaic PET scan on NMRI tumour-bearing nude mice treated or nor with MCT1 inhibitors AR-C155858 and AZD3965... [18F]-FLac is a promising PET radiotracer to detect oxidative tumours including those silent to 18FDG. This possibility is currently tested with slowly growing PC3 tumours and metastases in mice. [18F]-FLac could further be used alone or sequentially with 18FDG as a companion diagnostic for personalized treatments selectively targeting oxidative or glycolytic cancer cells."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • LDHB • SLC16A1

Investigating the Role of Lactate Import and Metabolism in Non-Small Cell Lung Cancer (IASLC-WCLC 2024) - "Cells were treated with the MCT1 inhibitor AZD3965 (100 uM) for 24h prior to the addition of physiological concentrations of glucose or lactate...By further mimicking physiological nutrient conditions, such as the use of HPLM, we are better able to model the metabolism of tumors in vivo. Further optimization of culture conditions can provide a foundation to understand the role of MCT1 inhibition as a therapeutic target for NSCLC."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • SLC16A1

Role of electrogenic and electroneutral monocarboxylate transport in airway clearance (NACFC 2024) - "Preliminary data indicated that MCT1 inhibitor (AZD3965) diminished this effect on MTV... These results indicate that monocarboxylates induce a Na +-coupled current in the mouse trachea and that SMCT1 mediates this activity. Mucociliary clearance (PTS and MTV) is not affected by SMCT1 activity, although MCT activity increases mucociliary clearance, possibly because removal of H+ from ASL alkalizes the airway surface. The use of MCT transportable substrates might help alleviate mucostasis in muco-obstructive diseases and will be tested in animal models of these diseases."

Infectious Disease • Inflammation • SLC5A1

Enhanced glycolysis causes extracellular acidification and activates acid-sensing ion channel 1a in hypoxic pulmonary hypertension. (PubMed, Am J Physiol Lung Cell Mol Physiol) - "Additionally, we found that intracellular alkalization and extracellular acidification occur in PASMC following CH, and in vitro hypoxia, which was prevented by inhibition of glycolysis with 2-deoxy-D-glucose (2-DG)...Although the putative monocarboxylate transporter 1 (MCT1) and -4 (MCT4) inhibitor, syrosingopine, prevented the pH shift; the specific MCT1 inhibitor, AZD3965, and/or the MCT4 inhibitor, VB124, were without effect, suggesting syrosingopine targets the glycolytic pathway independent of H+ export...These data suggest multiple H+ transport mechanisms contribute to extracellular acidosis and inhibiting glycolysis, rather than specific H+ transporters, more effectively prevents extracellular acidification and ASIC1a activation. Together, these data reveal a novel pathologic relationship between glycolysis and ASIC1a activation in hypoxic PHTN."

Journal • Cardiovascular • Hypertension • Metabolic Disorders • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • CA9 • SLC16A1