SAR131675 / Sanofi - LARVOL DELTA

Reversal of ABCG2-mediated MDR by VEGFR3 inhibitor (S)-SAR131675. (PubMed, Front Pharmacol) - "Through several experiments, we demonstrate that (S)-SAR131675 targets the efflux function of ABCG2, resulting in an increased intracellular concentration of substrates of ABCG2, including mitoxantrone and topotecan. Additionally, this resensitizing effect did not affect the overall protein expression or subcellular localization of ABCG2 in the ABCG2-overexpressing cell lines. In summary (S)-SAR131675 can overcome ABCG2-mediated MDR by directly suppressing the drug efflux function, providing a promising basis for the further development of cancer treatments associated with MDR in the future."

Journal • Breast Cancer • Colon Cancer • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ABCG2 • FLT4

Design and Biophysical Characterization of ¹⁸F-Labeled Small-Molecule Radioligands Targeting VEGFR-3 for PET Imaging of Tumor Lymphatic Activity (SNMMI 2026) - "Objective To design and biophysically characterize a series of SAR131675 analogs, in vitro evaluate the binding affinity for VEGFR-3 and selectivity over VEGFR-1 and VEGFR-2, radiolabel one representative compound with fluorine-18, and to preliminarily assess the radiotracer kinetics in healthy animals... We report the first series of ¹⁸F-labeled small-molecule radioligands that exhibit high binding affinity for VEGFR-3 and moderate to high selectivity towards VEGFR-2 and VEGFR-1. The radiotracer may enable quantitative PET imaging of lymphangiogenesis involved in the tumor environment. The next step will focus on evaluating the radiotracers in VEGFR3-overexpressing tumor models and enhancing the blood-brain barrier penetration to investigate brain lymphatic-associated disorders."

Hematological Malignancies • Lymphoma • Neuroblastoma • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • FLT1 • FLT4 • KDR

Design and Biophysical Characterization of ¹⁸F-Labeled Small-Molecule Radioligands Targeting VEGFR-3 for PET Imaging of Tumor Lymphatic Activity (SNMMI 2026) - "Objective To design and biophysically characterize a series of SAR131675 analogs, in vitro evaluate the binding affinity for VEGFR-3 and selectivity over VEGFR-1 and VEGFR-2, radiolabel one representative compound with fluorine-18, and to preliminarily assess the radiotracer kinetics in healthy animals... We report the first series of ¹⁸F-labeled small-molecule radioligands that exhibit high binding affinity for VEGFR-3 and moderate to high selectivity towards VEGFR-2 and VEGFR-1. The radiotracer may enable quantitative PET imaging of lymphangiogenesis involved in the tumor environment. The next step will focus on evaluating the radiotracers in VEGFR3-overexpressing tumor models and enhancing the blood-brain barrier penetration to investigate brain lymphatic-associated disorders."

Hematological Malignancies • Lymphoma • Neuroblastoma • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • FLT1 • FLT4 • KDR

Naringin affects VEGFC/TGF-β1 to mediate intercellular communication in MASH through coordinated Src and p38 MAPK pathways. (PubMed, Biochem Pharmacol) - "In HFD-induced MASH mice and Vegfc△hep genetic models, both NAR and the vascular endothelial growth factor receptor-3 (VEGFR3) inhibitor SAR131675 attenuated hepatic steatosis, inflammation, and fibrosis, concomitant with reduced hepatic VEGFC expression and improved liver-to-body weight ratios...This macrophage-derived TGF-β1 critically mediates hepatic stellate cells (HSCs) activation. These findings define the complete "Who/Where/How" pathogenic relay in MASH fibrosis and establish the VEGFC-VEGFR3-Src/p38 MAPK-TGF-β1 axis as the pharmacological target of NAR."

Journal • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • MRC1 • NOS2 • TGFB1 • VEGFC

Inhibiting VEGFC - mediated hepatocyte - macrophage regulatory axis contributes to protective effects of naringin against high - fat diet - induced hepatic fibrosis. (PubMed, Phytomedicine) - "Hepatocyte-derived VEGFC is a key contributor to NASH-related liver fibrosis, functioning by regulating macrophage migration and phenotypic switch. The hepatoprotective effect of NAR is partially mediated through the inhibition of the VEGFC-mediated hepatocyte-macrophage regulatory axis."

Journal • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • CCL2 • CCR2 • CX3CR1 • IL10 • VEGFC

Serotonin, a downstream effector of GLP-2, enhances lacteal contractility and lymph flow. (PubMed, Am J Physiol Gastrointest Liver Physiol) - "Experiment 2: 1) Placebo, 2) Serotonin, 3) Serotonin + MAZ-51 (a VEGFR3 inhibitor), 4) Serotonin + SAR131675 (a second VEGFR3 inhibitor)...Intravital imaging of a prospero-related homeobox 1-enhanced green fluorescent protein rat model was utilized to assess lacteal contractility after placebo or serotonin administration. We demonstrated that single-dose GLP-2 administration acutely increased serotonin concentration in plasma, serotonin enhanced lymph flow, lymph TG output and lacteal contractility, antagonism of the serotonin receptor decreases GLP-2-enhanced mesenteric lymph flow and TG output and inhibition of VEGFR3 abolished serotonin-induced lymph flow and TG output."

Journal • FLT4

Inhibition of VEGFR-3 by SAR131675 decreases renal inflammation and lymphangiogenesis in the murine lupus nephritis model. (PubMed, Cell Death Discov) - "This study suggests the therapeutic potential of targeting lymphatic proliferation by VEGFR-3 inhibition in lupus nephritis. Modulation of the lymphatic network may provide a novel approach to treating chronic inflammation and attenuating renal autoimmune response."

Journal • Preclinical • Glomerulonephritis • Immunology • Inflammation • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Systemic Lupus Erythematosus • FLT4 • IFNA1 • LYVE1 • MYD88 • TLR7

Proffered Paper: Reshaping Tumor-Vascular-Immune Crosstalk by VEGFR-3 Modulation in Breast Cancer Brain Metastases (EACR 2025) - "Cell tolerance to VEGFR-3 inhibitor (VEGFR-3i), SAR131675, was evaluated in vitro using increasing compound concentrations... These findings suggest that normalizing lymphatic vasculature through VEGFR3 modulation can reshape the tumor-immune-lymphatic landscape, fostering a more effective anti-tumor immune response and potentially enhancing immunotherapy efficacy."

IO biomarker • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • FLT4

Design and Synthesis of Fluorine-18 Labeled Small Molecular Radioligands for PET Imaging of VEGFR-3 in the Lymphatic System (SNMMI 2025) - "SAR131675 was modeled quite well, forming two hydrogen bond interactions with the hinge, another hydrogen bond deeper within the pocket, and good packing interactions in the groove (Figure 1). The ethoxymethyl group is deeply oriented downward into the pocket, where modifications to extend its length are not tolerated. Molecular docking data suggests that the amide part of SAR131675 may not engage in the VEGFR-3 boding pocket."

Oncology • Solid Tumor • FLT4

Design and Synthesis of Fluorine-18 Labeled Small Molecular Radioligands for PET Imaging of VEGFR-3 in the Lymphatic System (SNMMI 2025) - "SAR131675 was modeled quite well, forming two hydrogen bond interactions with the hinge, another hydrogen bond deeper within the pocket, and good packing interactions in the groove (Figure 1). The ethoxymethyl group is deeply oriented downward into the pocket, where modifications to extend its length are not tolerated. Molecular docking data suggests that the amide part of SAR131675 may not engage in the VEGFR-3 boding pocket."

Oncology • Solid Tumor • FLT4

Activation of VEGFR3 and MLC2 are Critical for GLP-2 Enhancement of Chylomicron Transport. (PubMed, Gastro Hep Adv) - "An intraduodenal lipid bolus was applied to the rats 5 hours before the following intraperitoneal (i.p.) administrations: 1) saline (placebo), 2) GLP-2, 3) GLP-2 + MAZ-51 (a VEGFR3 inhibitor), 4) GLP-2 + SAR131675 (a second VEGFR3 inhibitor), 5) GLP-2 + ML-7 (a MLCK inhibitor)...Furthermore, VEGFR3 inhibition blocked MLC2 activation. Our data suggest that the activation of VEGFR3 and MLC2 play critical roles in GLP-2's enhancement of chylomicron secretion and that VEGFR3 activation is an important intermediary step in GLP-2's activation of MLC2."

Journal • FLT4

Anti-lymphangiogenesis for boosting drug accumulation in tumors. (PubMed, Signal Transduct Target Ther) - "In the current research, we verified that anlotinib, a tyrosine kinase inhibitor with anti-lymphangiogenesis activity, and SAR131675, a selective VEGFR-3 inhibitor, effectively decreased the density of tumor lymphatic vessels in mouse cancer models, further enhancing drug accumulation in tumor tissue. Meanwhile, this strategy significantly reduced tumor metastasis and elicited stronger anti-tumor immune responses. Our work describes a new, clinically transferrable approach to augmenting intratumoral drug accumulation, which shows great potential to address the current, unsatisfactory efficacies of therapeutic drugs without introducing metastatic risk."

Journal • Lymphoma • Oncology • FLT4

SAR131675 exhibits anticancer activity on human ovarian cancer cells through inhibition of VEGFR-3/ERK1/2/AKT signaling pathway. (PubMed, Cell Signal) - "Our results reveal an anticancer activity of SAR131675 on the growth and migration of ovarian cancer cells, which may be through inhibiting VEGFR-3/ERK1/2/AKT pathway. SAR131675 may serve as an effective targeted drug for ovarian cancer."

Journal • Oncology • Ovarian Cancer • Solid Tumor • FLT4 • VEGFC

Dual FGFR and VEGFR inhibition synergistically restrain hexokinase 2-dependent lymphangiogenesis and immune escape in intrahepatic cholangiocarcinoma. (PubMed, J Gastroenterol) - "Dual FGFR and VEGFR inhibition inhibits lymphangiogenesis through suppression of c-MYC-dependent and HIF-1α-mediated HK2 expression, respectively. HK2 downregulation decreased glycolytic activity and further attenuated PD-L1 expression. Our findings suggest that dual FGFR and VEGFR blockade is an effective novel combination strategy to inhibit lymphangiogenesis and improve immunocompetence in iCCA."

IO biomarker • Journal • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • FGFR • FGFR1 • FLT4 • HIF1A • HK2 • MYC • PD-L1 • VEGFC

SAR131675, A SELECTIVE VEGFR3 INHIBITOR, AMELIORATES RENAL INFLAMMATION AND LYMPHANGIOGENESIS IN THE MURINE LUPUS NEPHRITIS MODEL. (ERA-EDTA 2023) - "Inhibition of VEGFR3 by SAR131672 decreases the resiquimod induced lupus nephritis model by regulating inflammation and lymphangio genesis."

Preclinical • Glomerulonephritis • Immunology • Inflammation • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • CCL19 • CCL21 • CCR7 • CXCL13 • FLT4 • ICAM1 • VCAM1

DC101, an anti-VEGFR2 agent, promotes high-endothelial venule formation and immune infiltration versus SAR131675 and fruquintinib. (PubMed, Biochem Biophys Res Commun) - "Moreover, DC101 enhanced the infiltration of dendritic cells and B cells, and local HEV formation. In conclusion, our data indicate that DC101 may be a better choice for the combined clinical application of ICIs and anti-angiogenic agents."

IO biomarker • Journal • Immune Modulation • Melanoma • Oncology • Solid Tumor • CD31 • CD8 • FLT4 • GZMB • HIF1A • IFNG • KDR • PD-1 • PD-L1 • PECAM1 • PTPRC

Dual FGFR and VEGFR Inhibition Synergistically Restrain Hexokinase 2-depenfent Lymphangiogenesis and Immune Escape in Intrahepatic Cholangiocarcinoma (APASL 2023) - "The therapeutic efficacy of infigratinib in combination with SAR131675 were assessed in LECs and xenograft models. Dual FGFR and VEGFR inhibition restrain lymphangiogenesis through suppression c-MYC-dependent and HIF-1α-mediated HK2 expression respectively. Decreased HK2 down-regulated glycolytic activity and further attenuated PD-L1 expression. Our findings suggest that dual FGFR and VEGFR blocking is an effective novel combination strategy to inhibit lymphangiogenesis and improve the immunocompetence in iCCA."

IO biomarker • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • FGFR • FGFR1 • FLT4 • HIF1A • HK2 • MYC • PD-L1 • VEGFC

Integrated profiling uncovers prognostic, immunological, and pharmacogenomic features of ferroptosis in triple-negative breast cancer. (PubMed, Front Immunol) - "The high-risk group had a higher response to anti-PD-1 blockade or sunitinib, and the low-risk group had higher sensitivity to cisplatin. Two Cancer Therapeutics Response Portal (CTRP)-derived agents (SNX-2112 and brefeldin A) and PRISM-derived agents (MEK162, PD-0325901, PD-318088, Ro-4987655, and SAR131675) were predicted, which were intended for high-risk patients. Altogether, our findings unveil prognostic, immunological, and pharmacogenomic features of ferroptosis in TNBC, highlighting the potential clinical utility of ferroptosis in TNBC therapy."

Biomarker • IO biomarker • Journal • Breast Cancer • Immunology • Oncology • Solid Tumor • Triple Negative Breast Cancer

Effect of electroacupuncture on myocardial inflammatory injury and apoptosis in mice with acute myocardial ischemia based on VEGF-C/VEGFR-3 pathway (PubMed, Zhongguo Zhen Jiu) - "EA could relieve the inflammatory reaction and apoptosis in AMI mice, and its mechanism may be related to activating VEGF-C/VEGFR-3 pathway and promoting lymphangion genesis."

IO biomarker • Journal • Preclinical • Cardiovascular • Hematological Malignancies • Lymphoma • Myocardial Ischemia • Oncology • BCL2 • CASP3 • FLT4 • IL23A • TNFA • VEGFC

Rotator cuff healing is regulated by the lymphatic vasculature. (PubMed, J Orthop Translat) - "Subsequently, the mice of experimental group were gavaged with the lymphatic inhibitors (SAR131675) on the first postoperative day to inhibit lymphangiogenesis, while the control group was treated with the vehicle...This is the first study to assess the specific role of lymphatic vessels in RC healing, and improving lymphatic drainage may be a potential new therapeutic approach to facilitate repair of BTI. Further, our study provides a reference for possible future treatment of BTI by intervening the lymphatic system."

Journal • Immunology • Inflammation

Electroacupuncture ameliorates inflammatory response of mice with acute myocardial ischemia by regulating vascular endothelial growth factor C/vascular endothelial growth factor receptor 3 pathway (PubMed, Zhen Ci Yan Jiu) - "Acupuncture can improve the inflammatory injury of AMI mice, which may be related to activate VEGF-C/VEGFR-3 pathway to promote lymphangiogenesis, reduce macrophage infiltration and inflammatory factors."

Journal • Preclinical • Cardiovascular • Inflammation • Myocardial Ischemia • CD68 • FLT4 • IL18 • IL6 • LYVE1 • TNNI3 • VEGFC

Aiphanol, a multi-targeting stilbenolignan, potently suppresses mouse lymphangiogenesis and lymphatic metastasis. (PubMed, Acta Pharmacol Sin) - "In addition, we found that aiphanol decreased the COX2-dependent secretion of PGE2 and VEGF-C from tumor cells and macrophages. These results demonstrate that aiphanol is an appealing agent for preventing lymphangiogenesis and lymphatic dissemination by synergistically targeting VEGFR3 and inhibiting the COX2-PGE2-VEGF-C signaling axis."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • FLT4 • KDR • VEGFC

SAR131675, a VEGRF3 Inhibitor, Modulates the Immune Response and Reduces the Growth of Colorectal Cancer Liver Metastasis. (PubMed, Cancers (Basel)) - "These results suggest that SAR131675 alters the immune composition within tumor and the surrounding liver in the later stages of development, resulting in a less immunosuppressive environment. This immunomodulation effect may contribute to the suppression of tumor growth."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Immune Modulation • Immunology • Inflammation • Oncology • Solid Tumor • CD8 • FLT4 • ITGAM • PD-1 • PD-L1 • PTPRC

Lymphangiogenesis contributes to exercise-induced physiological cardiac growth: Running title: Lymphangiogenesis in physiological hypertrophy. (PubMed, J Sport Health Sci) - "Our findings reveal that cardiac lymphangiogenesis is required for exercise-induced physiological cardiac growth by VEGFR3 activation, and they indicate that LEC-conditioned medium promotes both physiological hypertrophy and proliferation of cardiomyocytes through AKT activation and the C/EBPβ-CITED4 axis. These results highlight the essential roles of cardiac lymphangiogenesis in exercise-induced physiological cardiac growth."

Journal • FLT4 • IGF1 • LYVE1 • PDPN

VEGF-D-mediated signaling in tendon cells is involved in degenerative processes. (PubMed, FASEB J) - "On cultured rat tendon cells we show that VEGF-D stimulates cell proliferation in a dose-dependent manner; the specific VEGFR3 inhibitor SAR131675 reduces cell proliferation and cell migration...Together, these results suggest a strong role of tendon cell VEGF signaling in mediation of degenerative processes. These findings give novel insight into tendon cell biology and may pave the way for novel treatment options for degenerative tendon diseases."

Journal • Fibrosis • Immunology • FLT1 • FLT4 • KDR • VEGFD