GW441756 / Kanazawa Medical University - LARVOL DELTA

Unidirectional Crosstalk Between NTRK1 and IGF2 Drives ER Stress in Chronic Pain. (PubMed, Biomedicines) - " Using a skin/muscle incision-retraction (SMIR) rat model, we integrated molecular analyses and intrathecal targeting of NTRK1 (GW441756) or IGF2 (siRNA)...The NTRK1-IGF2-ER stress axis represents a novel therapeutic target; NTRK1 inhibitors and IGF2 biologics offer non-opioid strategies for precision analgesia. This work advances CPSP management and demonstrates how decoding unidirectional signaling hierarchies can transform neurological disorder interventions."

Journal • Addiction (Opioid and Alcohol) • CNS Disorders • Neuralgia • Pain • ER • IGF2 • NTRK • NTRK1

Combining xQTL and genome-wide association studies from ethnically diverse populations improves druggable gene discovery. (PubMed, Res Sq) - "Notably, experimental assays demonstrated that the NTRK1 protein inhibitor GW441756 significantly reduced tau hyper-phosphorylation (including p-tau181 and p-tau217) in AD patient-derived iPSC neurons, thus providing mechanistic support for our predictions. Overall, our findings underscore the power of gene-based association testing as a strategic tool for informed drug target discovery and validation based on human genetic and genomic data for complex diseases."

Journal • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Depression • Diabetes • Major Depressive Disorder • Metabolic Disorders • Psychiatry • Schizophrenia • Type 2 Diabetes Mellitus • NTRK1 • p-tau181 • RIPK2

Cellular Receptor Tyrosine Kinase Signaling Plays Important Roles in SARS-CoV-2 Infection. (PubMed, Pathogens) - "We showed that the HER2 inhibitor Lapatinib significantly reduced viral replication in both cell lines, the TrkA inhibitor GW441756 was effective only in A549-ACE2 cells, while the EGFR inhibitor Gefitinib had little effect in either cell line. Time-of-addition experiments indicated that Lapatinib may inhibit the early entry step, whereas GW441756 can affect post-entry steps of the viral life cycle. These findings suggest the important roles of HER2 and TrkA signaling in SARS-CoV-2 infection in human lung epithelial cells and support further investigation of RTK inhibitors as potential COVID-19 treatments."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Cisplatin induced alterations in nociceptor developmental trajectory elicits a TrkA dependent platinum-based chemotherapy induced neuropathic pain. (PubMed, Neuroscience) - "In vitro studies utilised isolated neonatal dorsal root ganglia sensory neurons treated with cisplatin (5 μg/ml) to elucidate impact upon nociceptor activation and neurite growth, in combination with TrkA inhibition (GW441756 10 nM and 100 nM). Administration of TrkA antagonist suppressed cisplatin induced TRPV1 mediated nociceptor sensitisation and prevented cisplatin induced neuropathic pain. These studies provide greater understanding of the underlying mechanisms that cause cisplatin induced childhood cancer survivorship pain and allowing identification of potential therapeutic targets."

Journal • CNS Disorders • Immunology • Neuralgia • Oncology • Pain • Pediatrics

Intervertebral disc injury triggers neurogenic inflammation of adjacent healthy discs. (PubMed, Spine J) - "This model supports a role of neurogenic inflammation in disc degeneration, and may play a role in the experience of low back pain."

Journal • Back Pain • Fibrosis • Inflammation • Lumbar Back Pain • Musculoskeletal Pain • Pain • ACAN • IL1B • IL6

Heart Failure Post-Myocardial Infarction Promotes Mammary Tumor Growth Through the NGF-TRKA Pathway. (PubMed, JACC CardioOncol) - "Notably, inhibition of TRKA by small interfering RNA or the chemical inhibitor GW441756 effectively blocked these effects...Our study demonstrates that MI promotes mammary tumor growth through the NGF-TRKA pathway. Consequently, inhibiting TRKA could represent a therapeutic strategy for breast cancer patients concurrently experiencing heart failure after MI."

Journal • Breast Cancer • Cardiovascular • Congestive Heart Failure • Heart Failure • Myocardial Infarction • Oncology • Solid Tumor • NGF

NGF contributes to activities of acid-sensing ion channels in dorsal root ganglion neurons of male rats with experimental peripheral artery disease. (PubMed, Physiol Rep) - "In addition, application of NGF onto DRG neurons increased the density of ASIC3 currents and the effect of NGF was significantly attenuated by TrkA antagonist GW441756. Moreover, the enhancing effect of NGF on the density of ASIC3-like currents was decreased by the respective inhibition of intracellular signaling pathways, namely JNK and NF-κB, by antagonists SP600125 and PDTC. Our results suggest contribution of NGF to the activities of ASIC3 currents via JNK and NF-κB signaling pathways in association with the exercise pressor reflex in experimental PAD."

Journal • Preclinical • Cardiovascular • Peripheral Arterial Disease • Reperfusion Injury • NGF

Myocardial Infarction Promotes Breast Cancer Growth Through the Nerve Growth Factor/Tropomyosin Receptor Kinase A Pathway (AHA 2023) - "The NGF/TRKA pathway is involved in accelerated tumor cell growth under MI-induced heart failure."

Breast Cancer • Cardiovascular • Congestive Heart Failure • Heart Failure • Myocardial Infarction • Oncology • Solid Tumor • NGF

The effect of Banxia-houpo decoction on CUMS-induced depression by promoting M2 microglia polarization via TrkA/Akt signalling. (PubMed, J Cell Mol Med) - "The above beneficial effect of BXHPD can be blocked by TrkA inhibitor GW441756. This work demonstrated that BXHPD exerted an anti-depressant effect by promoting M2 phenotype microglia polarization via TrkA/Akt pathway."

Journal • CNS Disorders • Depression • Inflammation • Mood Disorders • Psychiatry • AKT2 • ARG1 • IL10 • IL12A • IL1B • IL4 • IL6 • KDM6B • TNFA

Identification of a cancer-associated fibroblast classifier for predicting prognosis and therapeutic response in lung squamous cell carcinoma. (PubMed, Medicine (Baltimore)) - "In silico drug screening identified 6 effective compounds for high-risk CAFs-related LUSC: TAK-715, GW 441756, OSU-03012, MP470, FH535, and KIN001-266. Additionally, search tool for interaction of chemicals database highlighted PI3K-Akt signaling as a potential target pathway for high-risk CAFs-related LUSC. Overall, our findings provide a molecular classifier for high-risk CAFs-related LUSC and suggest that treatment with PI3K-Akt signaling inhibitors could benefit these patients."

IO biomarker • Journal • Non Small Cell Lung Cancer • Oncology • Squamous Cell Carcinoma • CAFs • KLF10 • PDGFA • SERPINE1 • SMAD7

Huntingtin-associated protein 1 ameliorates neurological function rehabilitation by facilitating neurite elongation through TrKA-MAPK pathway in mice spinal cord injury. (PubMed, Front Mol Neurosci) - "ERK activator U-46619 reverses the blocking effect of GW441756 on r-HAP1. HAP1 activates the TrkA-MAPK signaling pathway and is conducive to neurite elongation during NSC neuronal differentiation; by which to improve the prognosis of spinal cord injury in mice."

Journal • Preclinical • CNS Disorders • Huntington's Disease • Orthopedics

Nerve Growth Factor/Tropomyosin Receptor Kinase A Axis Plays a Pivotal Role in Breast Cancer Progression After Myocardial Infarction (AHA 2022) - "A TrkA inhibitor, GW441756, suppressed the NGF-induced phosphorylation of TrkA in 4T1 cells. Increased NGF caused by MI is associated with breast cancer progression through NGF/TrkA axis."

Breast Cancer • Cardiovascular • Congestive Heart Failure • Myocardial Infarction • Oncology • Solid Tumor • NGF

A five-cuproptosis-related LncRNA Signature: predicting prognosis, assessing immune function & drug sensitivity in lung squamous cell carcinoma. (PubMed, J Cancer) - "The drug sensitivity analysis showed that patients with low-risk ratings were likely to respond to GW441756 and Salubrinal. In contrast, patients with higher risk scores were more responsive to dasatinib and Z-LLNIe CHO. The 5-Cuprophosis-related lncRNA signature can be used to predict prognosis, assess immune function, and test drug sensitivity in LUSC patients."

Journal • Non Small Cell Lung Cancer • Oncology • Squamous Cell Carcinoma • IFNG

TrkA inhibition alleviates bladder overactivity in cyclophosphamide-induced cystitis by targeting hyperpolarization-activated cyclic nucleotide-gated channels. (PubMed, Iran J Basic Med Sci) - "To investigate the potential of Tropomyosin receptor kinase A (TrkA) for the treatment of interstitial cystitis/ bladder pain syndrome (IC/BPS). However, the inhibitory effects of GW441756 (10 μM) on the spontaneous contractions of detrusor muscle strips and the overall bladder activity were eliminated after pretreatments with the specific blocker of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, ZD7288 (50 μM). Our results suggested that increased TrkA expression during chronic cystitis promotes the development of bladder overactivity by targeting the HCN channels."

Journal • Interstitial Cystitis • Musculoskeletal Pain • Pain • IL6 • TNFA

Targeting the Nerve Growth Factor Signaling Impairs the Proliferative and Migratory Phenotype of Triple-Negative Breast Cancer Cells. (PubMed, Front Cell Dev Biol) - "The tropomyosin receptor kinase A inhibitor GW441756 reverses all these responses...Pharmacological inhibition of the tyrosine kinases Src and FAK (focal adhesion kinase), together with the silencing of β1-integrin, shows that the tyrosine kinases impinge on both proliferation and motility, while β1-integrin is needed for motility induced by nerve growth factor in triple-negative breast cancer cells. The present data support the key role of the nerve growth factor/tropomyosin receptor kinase A pathway in triple-negative breast cancer and offer new hints in the diagnostic and therapeutic management of patients."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • MMP9 • NGF