LY2109761 / Eli Lilly - LARVOL DELTA

Hypoxic Tumor Microenvironment Promotes Hippo Pathway Transcriptional Activity to Enrich Glioma Stem Cells in the Peri-necrotic Niche of Glioblastoma (SNO 2025) - "AKT inhibition with Capivasertib reduced Zyx phosphorylation and Hippo transcription in hypoxia...Blocking TGFBR2 with inhibitor LY2109761 abolished TGF-β1-induced Hippo activation...In vivo, pharmacologic inhibition of YAP/TAZ with Verteporfin or genetic TAZ knockdown in the RCAS/tv-a mouse model reduced tumor burden and prolonged survival. Flow cytometry confirmed decreased CD133+/CD44+ GSCs in TAZ-deficient tumors. These results demonstrate hypoxia and TGF-β1 signaling to activate YAP/TAZ-driven Hippo signaling, promoting GSC maintenance in the peri-necrotic GBM niche."

Biomarker • Tumor microenvironment • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • CCN1 • CD133 • FOXM1 • OLIG2 • SOX2 • TAFAZZIN • TGFB1 • TGFBR2 • YAP1

TET1 regulates self-renewal of porcine skin-derived stem cells through TGF-β signaling pathway. (PubMed, Cell Signal) - "Treating pSDSCs with LY2109761, a TGF-β signaling inhibitor, produced a phenotype similar to TET1 knockdown...Unlike previous studies that primarily emphasized the epigenetic role of TET1, this study reveals its functional link to a signaling pathway. These findings provide a deeper understanding of SDSCs and suggest that targeting the TET1-TGF-β axis may represent a promising approach to enhance the self-renewal capacity of SDSCs."

Journal • Preclinical • SMAD3 • TGFB1

Mitochondrial-targeted photodynamic therapy combined with TGF-β inhibition potentiates anti-PD-1 therapy in pancreatic ductal adenocarcinoma. (PubMed, J Nanobiotechnology) - "To address these challenges, we develop a liposomal nanodrug that co-encapsulates a mitochondrial-targeted photosensitizer (MP) and a TGF-β receptor inhibitor (LY2109761) to synergize PDT with PD-1 checkpoint blockade...In murine PDAC models, this dual-action strategy transforms the immune-cold TME into an immune-inflamed phenotype, sensitizing tumors to PD-1 therapy and leading to pronounced tumor regression and prolonged survival. Our findings present a promising nanodrug-based approach to remodel the fibrotic and immunosuppressive TME of PDAC and enhance immunotherapeutic outcomes."

Journal • Fibrosis • Immunology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • TGFB1

Hypoxic Tumor Microenvironment Promotes Hippo Pathway Transcriptional Activity to Enrich Glioma Stem Cells in the Peri-necrotic Niche of Glioblastoma (WFNOS 2025) - "AKT inhibition with Capivasertib reduced Zyx phosphorylation and Hippo transcription in hypoxia...Blocking TGFBR2 with inhibitor LY2109761 abolished TGF-β1-induced Hippo activation...In vivo, pharmacologic inhibition of YAP/TAZ with Verteporfin or genetic TAZ knockdown in the RCAS/tv-a mouse model reduced tumor burden and prolonged survival. Flow cytometry confirmed decreased CD133+/CD44+ GSCs in TAZ-deficient tumors. These results demonstrate hypoxia and TGF-β1 signaling to activate YAP/TAZ-driven Hippo signaling, promoting GSC maintenance in the peri-necrotic GBM niche."

Biomarker • Tumor microenvironment • Brain Cancer • Glioblastoma • Solid Tumor • CCN1 • CD133 • FOXM1 • OLIG2 • SOX2 • TAFAZZIN • TGFB1 • TGFBR2 • YAP1

Transforming Growth Factor Beta 1/SMAD2 Signalling Axis Regulates Leukemia Stem Cell Marker CD123: Implications for Acute Myeloid Leukemia (ASH 2024) - "Finally, looking at AML/MDS patient sample, we were able to show LY2109761 treatment result in striking reduction in IL3Rα and TGFβ1 responsive gene, ID1.Conclusion : In summary, our results highlight the critical role for the TGFβ1/SMAD2/SMAD4 signalling in skewing transcriptional machinery at the regulatory site of IL3Rα gene which prime progenitors toward inflammatory myelopoiesis. Understanding this TGFβ1 regulatory mechanism in upregulating CD123 may provide valuable insights for the future development of LSC-directed therapies, particularly in AML patients."

IO biomarker • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Inflammation • Leukemia • Myelodysplastic Syndrome • Oncology • CD123 • CD34 • ID1 • IL3RA • SMAD4 • TGFB1 • TGFB2

CD44 knockdown and TGF‑β inhibition modulate cell proliferation and invasion in claudin‑low breast cancer cells. (PubMed, Oncol Rep) - "CD44 was knocked down in claudin‑low breast cancer cell lines (SUM159 and MDA‑MB‑231), and the TGF‑β receptor (TGFBR) inhibitor LY2109761 (LY‑61) was applied for treatment...Although CD44 depletion may increase EMT‑related signaling, invasion was primarily suppressed by TGF‑β blockade, and the combination with CD44 knockdown further enhanced the inhibition of proliferative phenotypes compared with either treatment alone. This dual‑targeting approach warrants further investigation in claudin‑low breast cancer."

Journal • Breast Cancer • Oncology • Solid Tumor • ANXA5 • CD24 • CD44 • TGFB1

Butein attenuates cardiac fibrosis by mediating TGF-β1/Smad signaling pathway after myocardial infarction. (PubMed, J Mol Histol) - "Butein mitigated MI development by inhibiting cardiac fibrosis and ECM deposition by inactivating the TGF-β1/Smad signaling pathway."

Journal • Cardiovascular • Fibrosis • Immunology • Myocardial Infarction • TGFB1

Esaxerenone inhibits renal macrophage proliferation through MR/TGF-β1 pathway in db/db mice. (PubMed, Life Sci) - "Esaxerenone inhibits renal macrophage proliferation mediated by high glucose-induced activation of MR and downstream TGF-β1 signaling pathways, thereby mitigating inflammatory and fibrotic damage. These findings suggest that MR blockade may directly target macrophage proliferation and inflammation in DKD."

Journal • Preclinical • Diabetes • Diabetic Nephropathy • Fibrosis • Inflammation • Nephrology • Renal Disease • MRC1 • TGFB1

Autocrine TGF-β1 in Periodontal Ligament-Derived Stem Cell Pellets Enhances Periodontal Regeneration in Class II Furcation Defects of Canine Models. (PubMed, Adv Healthc Mater) - "However, LY2109761, an inhibitor of TGF-β receptor I and II, suppressed periodontal tissue regeneration in immunodeficient mice. In the beagle dog with Class II furcation defects, PDLSC-CP regenerated and repaired periodontal bone defects, which is more effective than the control group, the bone substitutes group, and the mixed group (PDLSC-CP and bone substitutes). These findings highlight PDLSC-CP as a promising strategy for periodontal bone defect treatment, where autocrine TGF-β1 stimulates the TGF-β1/Smad pathway to drive periodontal tissue regeneration."

Journal • Preclinical • TGFB1

Role of the TGF-β/SMAD pathway in tumor radioresistance to boron neutron capture therapy (BNCT) in a human cell line of colon adenocarcinoma. (PubMed, Appl Radiat Isot) - " The activation of the TGF-β/SMAD pathway and its interaction with the DNA repair via through ATR transductor was demonstrated. LY2109761 could act as a radiosensitizer for BNCT."

Journal • Preclinical • Colon Adenocarcinoma • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Solid Tumor • SMAD7 • TGFB1

EMP3 is upregulated upon epithelial-mesenchymal transition and contributes to EGFR-tyrosine kinase inhibitor resistance in lung adenocarcinoma. (PubMed, Eur J Med Res) - "Human LUAD cells HCC827 and H1975 were exposed to different doses of osimertinib or erlotinib to generate TKI-resistant cell lines. Notably, the LY2109761 treatment reduced TKI resistance and diminished expansion, migration, and stemness in cancer cells induced by EMP3 overexpression. In conclusion, this study indicates that EMP3, upregulated upon EMT, contributes to EGFR-TKI resistance in LUAD cells."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • TGFB1 • ZEB1

Enhancing the therapeutic efficacy of gemcitabine in bladder cancer through TGF-β1 inhibition and pluronic F-127-based microsphere delivery. (PubMed, J Biol Eng) - "The present research was designed to explore the impact of TGF-β1 inhibitors (LY2109761 and LY3200882) with or without gemcitabine on bladder cancer cells and to develop Pluronic F-127-based microspheres (MSs) for drug delivery. Systemic and local bladder toxicity assessments in mice demonstrated the in vivo safety of drug-loaded MSs. This study concludes that combining TGF-β1 inhibitors with gemcitabine in Pluronic F-127-based MSs enhances therapeutic efficacy against bladder cancer, promoting apoptosis, inhibiting cell invasion, and reducing tumor growth and metastasis while maintaining safety."

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • TGFB1

Overcoming PARP inhibitor resistance in triple-negative breast cancer models through olaparib and RAD51 inhibition with TGF-beta 2 downregulation (AACR 2025) - "RAD51 and PARP combinatory inhibition effectively overcomes Olaparib resistance in BRCA1-mutatnt and wild-type TNBC PDX models. RAD51 inhibition decreased expression of TGF-β2 in TNBC tumors, suggesting targeting RAD51 and TGF-β2 may be a potential therapeutic strategy to overcome Olaparib resistance in triple-negative breast cancer."

Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA1 • RAD51 • TGFB1 • TGFB2

Pharmacological Inhibition of Transforming Growth Factor Beta Receptor Improves Breathing Function and Cognition in Mice Models of Dementia (ISC 2025) - "LY2109761, a selective TGF-β receptor inhibitor, was administered orally every day for 6 weeks at a 50 mg/kg dose...TGFβR2 pharmacological inhibition additionally reduced astrogliosis in the RTN of Tg-2576 mice (drug 53.62±4.8 vs. vehicle 70.9±3.38, p=.018, n= 4/group).In conclusion, pharmacological inhibition of TGFβR2 improved cognition in AD and CAA mice. Improving breathing control via reducing gliosis at breathing center RTN may be the underlying mechanisms of the improvement."

Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Respiratory Diseases • GFAP • TGFBR2

Combination of polymeric micelle formulation of TGFβ receptor inhibitors and paclitaxel produces consistent response across different mouse models of Triple-negative breast cancer. (PubMed, Bioeng Transl Med) - "Here, we evaluated combination treatments using experimental TGFR inhibitors (TGFβi), SB525334 (SB), and LY2109761 (LY) with paclitaxel (PTX) chemotherapy. Genetic profiling of the tumors revealed differences in the expression levels of genes associated with TGFβ, epithelial to mesenchymal transition (EMT), TLR-4, and Bcl2 signaling, alluding to the susceptibility to specific gene signatures to the treatment. Taken together, our study suggests that TGFβi and PTX combination therapy using high-capacity POx micelle delivery provides a robust antitumor response in multiple TNBC subtype mouse models."

IO biomarker • Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BCL2 • TGFB1 • TGFBI • TLR4

NATURAL KILLER CELL-DERIVED EXTRACELLULAR VESICLES ALLEVIATE CD8+ T CELL EXHAUSTION IN ACUTE-ON-CHRONIC LIVER FAILURE VIA TGF-Β/SMAD PATHWAY (AASLD 2024) - "TβRI/II inhibitor LY2109761 or recombinant TGF-β were cultured with cells to regulate TGF-β/Smad pathway... The circulating CD8+ T cells in ACLF patients exhibit characteristics of exhaustion. NK-EVs alleviate CD8+ T cell exhaustion in ACLF via TGF-β/Smad pathway."

IO biomarker • Hepatology • Liver Failure • CD8 • CTLA4 • GZMB • LAG3 • PD-1 • PRF1 • TGFB1 • TIGIT

AMIGO2 enhances the invasive potential of colorectal cancer by inducing EMT. (PubMed, Cancer Gene Ther) - "Activation of the TGFβ/Smad signaling pathway was found involved in AMIGO2-induced EMT, and treatment with the TGFβ receptor inhibitor LY2109761 suppressed AMIGO2-induced EMT...These results suggest that the nuclear translocation of AMIGO2 induces EMT to promote CRC invasion by activating the TGFβ/Smad signaling pathway. Thus, AMIGO2 is an attractive therapeutic target for inhibiting EMT and metastatic CRC progression."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • AMIGO2 • HMGB1

Cellular senescence mediates retinal ganglion cell survival regulation post-optic nerve crush injury. (PubMed, Cell Prolif) - "Transforming growth factor-β receptor type II inhibitor (LY2109761) treatment suppressed p15Ink4b and p21Cip1 protein and SA-βgal expression and promoted RGC survival post-ON injury with decreasing the expression of cell death markers in retina. Consistently, senolytics (dasatinib and quercetin) treatments can promote RGC survival and alleviate the reduction of ganglion cell complex thickness and pattern electroretinography activity post-ON injury with reducing SA-βgal, p15Ink4b, p21Cip1, microglial activation and cell death marker expression. In summary, this study revealed the activation of cellular senescence in rodent retina post-ON injury and contribute to RGC survival regulation. Targeting cellular senescence can promote RGC survival after ON injury, suggesting a potential treatment strategy for traumatic optic neuropathy."

Journal • Inflammation • Ocular Inflammation • Ophthalmology • Optic Neuritis • Pain • CDKN1A

Dang-Gui-Si-Ni decoction facilitates wound healing in diabetic foot ulcers by regulating expression of AGEs/RAGE/TGF-β/Smad2/3. (PubMed, Arch Dermatol Res) - "In vivo, following establishment of DFU rat model, DSD intervention with low, medium and high doses was done, with Metformin (DM) as a positive control group. These effects were reversed after DSD intervention, and further LY2109761 intervention inhibited DSD effects in cells. DSD intervention may facilitate wound healing in DFU by regulating expression of AGEs/RAGE/TGF-β/Smad2/3, providing scientific experimental evidence for DSD clinical application for DFU therapy."

Journal • Diabetes • Metabolic Disorders • IL1B • IL6 • SMAD2 • SMAD3 • TGFB1 • TNFA

4-octyl itaconate inhibits high glucose induced renal tubular epithelial cell fibrosis through TGF-β-ROS pathway. (PubMed, J Recept Signal Transduct Res) - "In this current study, we observed that in human renal tubular epithelial cells (HK2), high glucose induced an increase in transforming growth factor β (TGF-β) production, and upregulated the expressions of fibronectin and collagen I through the TGF-β receptor as verified by administration of TGF-β receptor blocker LY2109761...In addition, we found that 4-OI exerted its anti-fibrotic effect by inhibiting the excessive production of ROS induced by high glucose and TGF-β. In summary, 4-OI could ameliorate high glucose-induced pro-fibrotic effect in HK2 cell, and blocking the expression of TGF-β and reducing the excessive ROS production may be involved in its anti-fibrotic effect."

Journal • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Fibrosis • Immunology • Metabolic Disorders • Nephrology • Renal Disease • FN1 • TGFB1

17β-Estradiol blocks hydrogen peroxide-induced senescence and apoptosis in human umbilical vein endothelial cells via targeting THBS1/TGF-β/Smad signaling pathway (ISGE 2024) - "Hydrogen peroxide (H2O2), drugs that modulate estrogen activity, and LY2109761 (TGF-β kinase inhibitor) were used for various treatments... Our findings demonstrated that 17β-E2 inhibits H2O2-induced oxidative stress by downregulating the expression level of THBS1 and subsequent TGF-β/Smad signaling in HUVECs. The THBS1/TGF-β/Smad axis could thus be a therapeutic target for CVDs."

Cardiovascular • ANXA5 • CDKN1A • CDKN2A • TGFB1

Inactivation of the TGF-β1/ALK5 axis enhances club cell function and alleviates lung tissue damage to ameliorate COPD progression through the MEK/ERK signaling pathway. (PubMed, Gen Physiol Biophys) - "The COPD mice were further divided into COPD group, DMSO group, and LY2109761 group (injected with 150 mg/kg LY2109761, a TGF-β1 inhibitor)...Inactivation of the TGF-β1/ALK5 axis inhibits the MEK/ERK signaling pathway, enhances club cell function, and alleviates lung tissue damage. These findings suggest that TGF-β1 is a potential therapeutic target for COPD."

Journal • Chronic Obstructive Pulmonary Disease • Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • CASP3 • CHEK1 • IFNG • IL12A • IL13 • IL4 • IL5 • TGFB1 • TGFBR1

Pirfenidone inhibits TGF-β1-induced metabolic reprogramming during epithelial-mesenchymal transition in non-small cell lung cancer. (PubMed, J Cell Mol Med) - "To elucidate the underlying mechanism, we compared the efficacy of PFD after pretreatment with either TGF-β1 or a TGF-β receptor inhibitor (LY2109761). Additionally, PFD combined with cisplatin targeted TGF-β1 to inhibit glycolysis during EMT and enhanced the chemosensitization of A549 and H1299 cells. The magnitude of the anticancer effect exhibited by PFD was intricately linked to its metabolic properties."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor • TGFB1

Differentiation of Uc-MSCs into insulin secreting islet-like clusters by trypsin through TGF-beta signaling pathway. (PubMed, Differentiation) - "Results show that induction efficacy was reached to 98% and TGF-β signaling pathway may play critical role in the early stage differentiation, it was further confirmed that the retardant effect of differentiation progress either in cell morphology or in islet specific genes expression can be observed upon blocking the activation of TGF-β signaling pathway using specific inhibitor of LY2109761 (TβRI/II kinase inhibitor). Our current study, for the first time, development a protocol for differentiation of Uc-MSCs into islet-like clusters, and revealed the importance of TGF-β signaling pathway in the early stage of differentiation of Uc-MSCs into islet-like clusters. Our study will provide alternative approach for clinical treatment of either type I or type II diabtes mellitus with dysfunctional pancreatic islets."

Journal • Diabetes • Gastrointestinal Disorder • Hepatology • Metabolic Disorders • Transplantation • Type 2 Diabetes Mellitus • TGFB1

Primary cilium participates in radiation-induced bystander effects through TGF-β1 signaling. (PubMed, J Cell Physiol) - "The TGF-β1 signaling was interfered by LY2109761, a TGF-β receptor 1 (TβR1) inhibitor, or TGF-β1 neutral antibody...IFT88 siRNA or KIF3a siRNA impaired PC formation resulted in an aggravated DNA damage in bystander cells, while elevated PC formation by CytoD or STIL siRNA resulted in a decrease of DNA damage. Furthermore, TGF-β1 induced more DNA damages in S phases cells which showed lower PC formation rate and less DNA damages in G /G phase cells which showed higher PC formation rate. This study demonstrates the particular role of primary cilia during RCM induced DNA damages through TGF-β1 signaling restriction and thereby provides a functional link between primary cilia and RIBEs."

Journal • Oncology • CDKN1A • TGFB1 • TP53BP1