AG1478 / IDT Australia - LARVOL DELTA

GPER and EGFR cross-talk highlight aldosterone- and MR antagonist-induced NO production in cultured endothelial cells. (PubMed, Front Pharmacol) - "All three MR antagonists blocked the aldosterone responses, yet each also evoked intrinsic, concentration-dependent NO production in the absence of aldosterone, eplerenone and spironolactone showing greater intrinsic efficacy than finerenone. Pretreatment with 100 nM of the GPER antagonist G-36 or 100 nM AG-1478 significantly reduced both aldosterone-induced DAF-NO signaling and vasodilation, whereas endothelium removal or L-NAME converted vasodilation into vasoconstriction...Because recent cryo-EM work reveals a non-canonical extracellular GPER architecture, the docking results are interpreted as structurally plausible interaction scenarios rather than definitive orthosteric assignments; whether the behaviour reflects direct partial agonism at GPER or an indirect, GPER-dependent mechanism remains to be established by direct-binding studies. These findings expand current understanding of MR antagonist pharmacology."

Journal • Cardiovascular • EGFR

Ranolazine inhibits invasiveness of human breast cancer cells in combination with a tyrosine kinase inhibitor: Dose-dependent synergy. (PubMed, J Pharmacol Exp Ther) - "Here, we aimed to test whether cotreatment of a model TNBC cell line, MDA-MB-231, with an epidermal growth factor receptor inhibitor (AG1478 [AG]) and RAN would produce a synergistic effect on invasiveness. These findings raise the possibility of treating triple-negative breast cancer nontoxically while reducing the chance of developing drug resistance. The results are also potentially applicable to multiple carcinomas."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • EGFR

Loganin Ameliorates Cholestatic Liver Fibrosis by Inhibiting Hepatic Stellate Cell Autophagy and Activation Through EGFR Signaling. (PubMed, Mediators Inflamm) - "Critically, cotreatment with the EGFR agonist EGF reversed the autophagy-inhibitory and antifibrotic effects of loganin, whereas the EGFR inhibitor AG-1478 mimicked loganin's actions, confirming EGFR signaling as the functional mediator. Overall, these results indicated that loganin could alleviate liver injury and hepatic fibrosis in BDL rats by inhibiting autophagy and activation of HSCs, and this protective effect is mediated by the EGFR pathway."

Journal • Fibrosis • Gastroenterology • Hepatology • Immunology • Liver Cirrhosis • Liver Failure • BECN1 • COL1A1 • TGFB1

FGF7 mitigates airway inflammation and epithelial injury in cigarette smoke-induced COPD model. (PubMed, Front Immunol) - "In the CSE-injured 16HBE cell model, recombinant FGF7 was applied with or without SB202190 (a p38 inhibitor), LY294002 (a PI3K inhibitor), or AG1478 (an EGFR inhibitor) to evaluate cell viability, migratory capacity, cytokine production, and activation of corresponding signaling pathways. It mitigates CS-induced airway epithelial damage and inflammation through the ADAM17-dependent EGFR-ERK1/2 axis, p38, and PI3K/AKT pathways. FGF7 therefore emerges as a promising therapeutic target for interventions aimed at preventing airway remodeling in COPD."

Journal • Chronic Obstructive Pulmonary Disease • Fibrosis • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • ADAM17 • FGF7 • IL1B • IL6 • TGFB1 • TNFA

Protective Role of NRG1/ErbB4 Signaling in Myocardial Ischemia-Reperfusion Injury. (PubMed, J Vis Exp) - "This study aimed to elucidate the molecular mechanisms by which the NRG1/ErbB4 pathway confers protection in a rat model of myocardial ischemia-reperfusion (MIRI) injury. A rat MIRI model was established, involving 30 adult male Sprague-Dawley rats randomly assigned to five groups: control, sham operation, MIRI, recombinant NRG1, and AG1478...The NRG1/ErbB4 signaling pathway plays a pivotal protective role in MIRI in rats. Supplementation with exogenous NRG1 effectively elevates NRG1 levels in the heart, activates the ErbB4 signaling pathway, reduces myocardial cell apoptosis, and decreases ROS levels, thereby mitigating MIRI-induced damage."

Journal • Cardiovascular • Inflammation • Myocardial Ischemia • Reperfusion Injury • NRG1

Phosphoproteomic analysis reveals the diversity of signaling behind ErbB-inhibitor-induced phenotypes. (PubMed, FEBS J) - "Here, we performed a phosphoproteomic analysis in embryonic zebrafish to identify the signaling pathways perturbed by ErbB receptor tyrosine-protein kinase inhibitors gefitinib, lapatinib, and AG1478 at the organism level. The treatment with the inhibitors targeting the PI3K/Akt, p38 MAPK, and Notch signaling pathways, along with the ErbB inhibitors AG1478 and lapatinib, perturbed the overall movement and ventricle wall growth of zebrafish embryos. Taken together, these results indicate that inhibitors with overlapping primary targets can affect different signaling pathways while eliciting similar physiological phenotypes."

Journal

Determination of survival associated genetic biomarkers to discover novel therapeutic targets for acute myeloid leukaemia. (PubMed, J Chemother) - "Drug repurposing using the LINCS L1000CDS2 database highlighted potential therapeutics, including 16-Hydroxytriptolide and Tryptosthin AG-1478, with roles in reversing hazardous gene expression patterns. Additional candidates such as Vemurafenib, Parthenolide and Wortmannin, demonstrated promise as targeted agents. These findings underscore the potential of integrating bioinformatics and drug discovery to identify precision medicine in AML. Further studies are warranted to validate these targets and explore their clinical utility."

Biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ZBTB16

Pretreatment of cancer cells with inhibitors of PKCδ, EGFR, and JNK increased intracellular hypericin content and enhanced the effectiveness of photodynamic therapy. (PubMed, J Photochem Photobiol B) - "We assessed the effects of inhibitors of epidermal growth factor receptor (EGFR) (Tyr - tyrphostin AG 1478) and c-Jun N-terminal kinase (JNK) (SP - SP600125, Lico - licochalcone A), as well as protein kinase C (PKC) activator (TPA) and inhibitor (Rot - rottlerin). More importantly, the sensitizing effects of the inhibitors were linked to increased intracellular HY accumulation, indicating reduced BCRP efflux activity. While the exact mechanisms behind these effects require further investigation, our findings suggest that targeting BCRP and associated signaling pathways could enhance PDT outcomes in cancer treatment."

Journal • Breast Cancer • Oncology • Solid Tumor • EGFR • MAPK8

Polystyrene nanoplastics aggravate house dust mite induced allergic airway inflammation through EGFR/ERK-dependent lung epithelial barrier dysfunction. (PubMed, Ecotoxicol Environ Saf) - "Furthermore, an EGFR-specific inhibitor AG1478 was employed to confirm the role of the EGFR/ERK pathway in lung epithelial barrier dysfunction and asthma exacerbation in vitro and in vivo experiments. In conclusion, the molecular mechanism by which PS-NPs aggravates asthma in mice was elucidated, which helps to improve the understanding of the health effects of PS-NPs and lays a theoretical foundation for addressing the health risks posed by PS-NPs."

Journal • Asthma • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • EGFR • IL13 • IL4

Cell-cell communication shapes the impact of obesity-associated stressors on human vascular cells. (ESPE-ESE 2025) - "Incubation of cells with either or both stimuli in the presence of AG1478/EGF revealed that MS-induced cell proliferation, dglucose, dlactate and ATP production seems to be EGFR dependent... This study indicates that the transcriptome and functional profile of cells are profoundly influenced by the cell culture type, underscoring the critical role of cell interactions in cellular behavior. The effects of MS in different vascular cells are, at least partially, mediated by EGFR. In few cases, these effects are further altered by HS."

Cardiovascular • Genetic Disorders • Inflammation • Obesity • EGFR

Activation of GPER1 alleviates white matter injury by promoting microglia M2 polarization through EGFR/Stat3 pathway in intracerebral hemorrhage mice. (PubMed, J Stroke Cerebrovasc Dis) - "Collectively, our findings demonstrated activation of GPER1 alleviated WMI via modulating microglia M2 polarization after ICH through EGFR/Stat3 signaling pathway."

Journal • Preclinical • Cerebral Hemorrhage • Hematological Disorders • Inflammation • Solid Tumor • GPER1 • IL10 • IL1B • IL4 • TNFA

Assessing the impact of CD73 inhibition on overcoming anti-EGFR resistance in glioma cells. (PubMed, Oncol Res) - "The U251 GB cell line was treated with AG1478, an EGFR inhibitor, and the resistance markers MRP-1, PD-L1, and CD73 were evaluated using flow cytometry...In summary, our findings indicate that CD73 inhibition has a modest effect in overcoming resistance to EGFR monotherapy in vitro. Thus, further in vivo studies are needed, as the inhibition of both EGFR and CD73 affects cells in the tumor microenvironment and could potentially enhance anti-tumor immunity."

IO biomarker • Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • CD73 • CTLA4 • NT5E • PD-L1

A Macrophage-smooth Muscle Cell Axis Influences Vascular Remodeling Through Activation of the EGFR Pathway in Giant Cell Arteritis (ACR Convergence 2024) - P=N/A | "Conversely, AG1478, an EGFR inhibitor, completely inhibited both VSMC migration and proliferation, suggesting a key role for the EGFR pathway in VSMC proliferation and migration. Our study shows that both AREG and HBEGF may play a role in the pathophysiology of GCA, especially in the remodeling phase of the disease. Further studies are needed to explore other EGFR ligands and to decipher the pathophysiological mechanisms between macrophages, VSMC and fibroblasts in GCA."

Giant Cell Arteritis • Immunology • Inflammation • Vasculitis • AREG • GLI2 • HBEGF

Transactivation of the EGF receptor as a novel desensitization mechanism for G protein-coupled receptors, illustrated by dopamine D2-like and β2 adrenergic receptors. (PubMed, Cell Mol Biol Lett) - "The EGFR inhibitor AG1478 prevented both desensitization and the associated cellular events...These findings suggest that EGFR transactivation diversifies pathways involved in ERK activation through the EGFR signaling system and also mediates GPCR desensitization. Alongside the widely accepted steric hindrance model, these findings offer new insights into understanding the mechanisms of GPCR desensitization, which occurs through complex cellular processes."

Journal • Targeted Protein Degradation

The influence of the NRG1/ERBB4 signaling pathway on pulmonary artery endothelial cells. (PubMed, Pulm Circ) - "NRG1 inhibition in HPAECs apoptosis can be partially reversed by inhibiting ERBB4 expression with AG1478. ERBB4 has the potential to be a novel biological marker of PE."

Journal • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Pulmonary Embolism • Respiratory Diseases • NRG1 • PI3K

Silencing Nrf2 in cisplatin resistant non-small cell lung cancer cells augments sensitivity towards EGFR inhibitor. (PubMed, Toxicol In Vitro) - "Recently, non-small cell lung cancer (NSCLC) has been the prime concern of cancer clinicians due to its high mortality rate worldwide. Moreover, genetic inhibition of Nrf2 with siRNA in CisR cells showed increased sensitivity towards the EGFR tyrosine kinase inhibitor (TKIs), AG1478. Our study, therefore suggests the use of Nrf2 inhibitors in combinatorial therapy with EGFR TKIs for the treatment of resistant NSCLC."

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

Recombinant tissue plasminogen activator protects neurons after intracerebral hemorrhage through activating the PI3K/AKT/mTOR pathway. (PubMed, Neural Regen Res) - "Moreover, the phosphoinositide 3-kinase inhibitor LY294002 abrogated the neuroprotective effects of recombinant tissue plasminogen activator in inhibiting excessive apoptosis, autophagy, and endoplasmic reticulum stress. It has been revealed that the epidermal growth factor receptor inhibitor AG-1478 reversed the effect of recombinant tissue plasminogen activator on the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway. These findings suggest that recombinant tissue plasminogen activator exerts a direct neuroprotective effect on neurons following intracerebral hemorrhage, possibly through activation of the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway."

Journal • Cerebral Hemorrhage • Hematological Disorders • EGFR

Lacticaseibacillus rhamnosus GG alleviates sleep deprivation-induced intestinal barrier dysfunction and neuroinflammation in mice. (PubMed, Food Funct) - "In terms of mechanism, it was found that AG1478, an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, could diminish the protective effects of LGG. In conclusion, LGG demonstrated the ability to alleviate SD-induced intestinal barrier dysfunction through EGFR activation and alleviate neuroinflammation."

Journal • Preclinical • CNS Disorders • Inflammation • Mental Retardation • Psychiatry • EGFR

PAR2 activation on human tubular epithelial cells engages converging signaling pathways to induce an inflammatory and fibrotic milieu. (PubMed, Front Pharmacol) - "A TGF-β receptor-1 (TGF-βRI) kinase inhibitor, SB431542, and an EGFR kinase inhibitor, AG1478, ameliorated 2F induced secretion of TNF, CSF2, MMP-9, and PAI-1. Whilst an EGFR blocking antibody, cetuximab, blocked PAR2 induced EGFR and ERK phosphorylation, a TGF-βRII blocking antibody failed to influence PAR2 induced secretion of PAI-1...In summary PAR2 activates critical inflammatory and fibrotic signalling pathways in human kidney tubular epithelial cells. Biased antagonists of PAR2 should be explored as a potential therapy for CKD."

Journal • Chronic Kidney Disease • Fibrosis • Immunology • Inflammation • Nephrology • Renal Disease • CSF2 • CTGF • GPRC6A • MMP9 • SMAD2 • TGFB1

Insights into Halogen-Induced Changes in 4-Anilinoquinazoline EGFR Inhibitors: A Computational Spectroscopic Study. (PubMed, Molecules) - "EGFR inhibitors like AG-1478 and PD153035, featuring a 4-anilinoquinazoline moiety, have garnered global attention for their potent therapeutic activities...Additionally, optical spectral shifts correlate with potency, as TKI-Cl and TKI-Br exhibit blue shifts from their global minimum structures, in contrast to other TKI-X. This suggests that optical reporting can effectively probe drug potency and conformation changes."

Journal • Oncology

The roles of tight junction protein cingulin in human endometrioid endometrial cancer. (PubMed, Tissue Barriers) - "In 2D and 2.5D cultures, treatment with β-estradiol with or without EGF or TGF-β decreased CGN expression and the epithelial permeability barrier and enhanced cell migration, and pretreatment with EW7197+AG1478, U0126 or an anti-IL-6 antibody prevented this. In conclusion, CGN, with tTJ proteins might suppress the malignancy of human EEC and its complex proteins are sensitive to estrogen and growth factors derived from stromal cells."

Journal • Endometrial Cancer • Oncology • Solid Tumor • CGN • EGF • LSR • TGFB1

EGFR/TKIs induce excessive apoptosis of bladder carcinoma cells by arresting cell cycle and promoting mitochondrial peroxidation damage. (PubMed, Cell Mol Biol (Noisy-le-grand)) - "Besides, the research team further observed that AG1478 also promoted pyroptosis in T24 cells, and its mechanism is related to the induction of mitochondrial oxidative stress damage. The findings lay a more reliable foundation for the future application of EGFR-TKIs in BC."

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

Effects of PM2.5 on mucus hypersecretion in airway through miR-133b-5p/EGFR/Claudin1/MUC5AC axis. (PubMed, Aging (Albany NY)) - "PM2.5 inhibited the expression of miR-133b-5p to activate the EGFR/MAPK signal pathway, induce the hypersecretion of MUC5AC, thus aggravating PM2.5-related airway inflammation in rats."

Journal • Inflammation • Respiratory Diseases • CLDN1 • EGFR • MIR133B • MUC5AC • TNFA

17-β-estradiol and phytoestrogens elicit NO production and vasodilatation through PI3K, PKA and EGF receptors pathways, evidencing functional selectivity. (PubMed, Eur J Pharmacol) - "Multiple estrogen receptor activity was inferred based on the reduction of DAF-NO signals; G-36 (GPER antagonist) reduced 75 % of all estrogen responses, while fulvestrant (selective nuclear receptor antagonist) reduced significantly more the phytoestrogens responses than E2...Wortmannin or LY-294002 (PI3K inhibitors), reduced by 90% the E2-evoked signal while altering significantly less the DAI-induced response...Epidermal growth factor (EGF) induced NO production, cell treatment with AG-1478, an EGF receptor kinase inhibitor reduced 90% DAI-induced response while only 53% the E2-induced signals; highlighting GPER induced EGF receptor trans-modulation. Receptor functional selectivity may explain distinct signalling pathways mediated by E2 and phytoestrogens."

Journal

EGF-like growth factors upregulate pentraxin 3 expression in human granulosa-lutein cells. (PubMed, J Ovarian Res) - "In addition, we found that the upregulation of PTX3 expression triggered by the EGF-like factors was completely reversed by either pretreatment with the epidermal growth factor receptor (EGFR) inhibitor, AG1478, or knockdown of EGFR, suggesting that EGFR is crucial for activating the ERK1/2 signaling pathway in hGL cells. Overall, our findings indicate that AREG, BTC, and EREG may modulate human cumulus expansion during the periovulatory stage through the upregulation of PTX3."

Journal • BTC • EGF • EREG • PTX3