PF-8380 / Pfizer - LARVOL DELTA

A novel strategy for sorafenib-resistant hepatocellular carcinoma: autotaxin Inhibition by PF-8380. (PubMed, J Cancer Res Clin Oncol) - "These effects were consistently observed in the orthotopic HCC mouse model, reinforcing PF-8380's potential as a dual inhibitor of EMT and autophagy in HCC treatment. Our research indicates that PF-8380 could provide substantial therapeutic benefits in the treatment of HCC, even in cases resistant to sorafenib, primarily by suppressing both EMT and autophagy processes."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • CDH1

ENPP2 promotes progression and lipid accumulation via AMPK/SREBP1/FAS pathway in chronic lymphocytic leukemia. (PubMed, Cell Mol Biol Lett) - "Taken together, our findings unravel the lipid metabolism characteristics of CLL. Moreover, we demonstrate a previously unidentified role and mechanism of ENPP2 in regulation of lipid metabolism, providing a novel therapeutic target for CLL treatment."

Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Metabolic Disorders • Oncology • AMPK • ENPP2 • FASN

Autotaxin-Specific PET/CT Imaging using [18F]ATX-1905 for Progression Monitoring and Efficacy Evaluation in Preclinical Models with Pulmonary Fibrosis (EANM 2024) - "To assess treatment efficacy, mice received oral administration of two commonly used drugs for IPF, pirfenidone or nintedanib, from Day 9 to Day 23 post-bleomycin administration...This heightened lung uptake was mitigated by pretreatment with the ATX inhibitor, PF-8380... PET imaging with [18F]ATX-1905 demonstrated outstanding capabilities in early fibrosis detection, disease monitoring, and treatment assessment within the lungs of BPF mouse models. Its notable specificity for ATX expression and sensitivity to ATX alterations indicate its potential for monitoring diverse ATX expression levels in the lungs of IPF patients."

Preclinical • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases

Imaging Pulmonary Fibrosis and Treatment Efficacy In Vivo with Autotaxin-Specific PET Ligand [18F]ATX-1905. (PubMed, Mol Pharm) - "The objective of this study was to evaluate the effectiveness of 18F-labeled ATX-targeted tracer [18F]ATX-1905, in comparison with [18F]FDG, for early fibrosis diagnosis, disease evolution monitoring, and treatment efficacy assessment in bleomycin-induced pulmonary fibrosis (BPF) models. To assess treatment efficacy, mice were treated with two commonly used drugs for IPF, pirfenidone or nintedanib, from Day 9 to Day 23 postbleomycin administration...This uptake was inhibited by an ATX inhibitor, PF-8380, underscoring the specificity of the radiotracer...Using our novel ATX-specific radiotracer [18F]ATX-1905 and PET/CT imaging, we demonstrated excellent ability in early fibrosis detection, disease monitoring, and treatment assessment within lungs of the BPF mouse models. [18F]ATX-1905 displayed remarkable specificity for ATX expression and high sensitivity for ATX alterations, suggesting its potential for monitoring varying ATX expression in lungs of IPF patients."

Journal • Preclinical • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases

Autotaxin Inhibition Reduces Post-Ischemic Myocardial Inflammation via Epigenetic Gene Modifications. (PubMed, Stem Cell Rev Rep) - "C57BL/6 J mice underwent left anterior descending coronary artery ligation to induce MI and were treated with the ATX inhibitor, PF-8380, or vehicle...Targeting ATX/LPA signaling may represent a novel therapeutic strategy to control inflammation and improve outcomes after MI. Further research is needed to validate these findings in preclinical and clinical settings and to elucidate the complex interplay between epigenetic mechanisms and ATX/LPA signaling in the context of MI."

Journal • Cardiovascular • Inflammation • Myocardial Infarction • HDAC5 • PRMT5

Autotaxin-Specific PET/CT Imaging in a Preclinical Model of Pulmonary Fibrosis (SNMMI 2024) - "To assess treatment efficacy, mice received oral administration of two commonly used drugs for IPF, pirfenidone or nintedanib, from D9 (Day 9) to D23 (Day 23) post-bleomycin administration...The target binding specificity of [18F]ATX-1905 was investigated through blocking experiments utilizing an ATX inhibitor, PF-8380... The PET tracer [18F]ATX-1905 exhibited excellent ability in early fibrosis detection, monitoring fibrosis progression, and assessing treatment outcomes of lungs in PET imaging of the mouse model with pulmonary fibrosis. Additionally, non-invasive PET imaging with [18F]ATX-1905 showed a high specificity in identifying alterations in ATX expression within the mouse lungs. All these findings suggest the promising potential of [18F]ATX-1905 as a tracer for future applications in monitoring IPF patients with varying ATX expression in lungs."

Preclinical • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases

Pharmacological Inhibition of Lysophosphatidic Acid Reduces Inflammation and Enhances Myocardial Recovery After Acute Infarction in Diet-Induced Obese Mice (AHA 2022) - "MI was associated with an increased number of circulating inflammatory monocytes (CD45+/Ly6C+/CD115+), as well as cardiac total and pro-inflammatory macrophages (CD45+/F4-80+/CD11b+/CD86+), as assessed by flow cytometry (Fig. 1A). This effect was exacerbated in HFD-fed mice but significantly attenuated in HFD+PF8380 treated mice with effective ATX inhibition."

Preclinical • Cardiovascular • Congestive Heart Failure • Coronary Artery Disease • Genetic Disorders • Heart Failure • Inflammation • Myocardial Infarction • Obesity • CD86 • ITGAM • PTPRC

A novel orally available type IV autotaxin inhibitor, IOA-289, ameliorates steatosis and fibrosis in a preclinical model of non-alcoholic steatohepatitis (EASL-ILC 2023) - "In the last six weeks, IOA-289 (30 mg/kg) or PF-8380 (a type-I ATX inhibitor, 30mg/kg) was orally administered twice daily. Our results demonstrate that inhibition of the LPA-ATX pathway, particularly using a type IV inhibitor, represents a potential therapeutic target in NASH, by attenuating steatosis and fibrosis, with possible clinical implications."

Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Non-alcoholic Steatohepatitis • ACACA • ACTA2 • FASN • PDGFRB • TGFB1

The Autotaxin-LPA Axis Emerges as a Novel Regulator of Smooth Muscle Cell Phenotypic Modulation during Intimal Hyperplasia. (PubMed, Int J Mol Sci) - "Treatment with an ATX inhibitor (PF8380) or LPA receptor inhibitor (Ki16425) attenuated VSMC proliferation (extracellular signal-regulated kinases) activity and migration in response to recombinant ATX...The upregulation of ATX following vessel injury leads to LPA production in VSMCs, favoring restenosis. Our observations suggest that inhibition of the ATX-LPA axis could be therapeutically targeted in restenosis to minimize VSMC phenotypic modulation and inflammation after vascular injury."

Journal • Immunology • Inflammation

Investigation of Lipid Metabolism Dysregulation in Chronic Lymphocytic Leukemia and the Role of ENPP2 in Tumorigenesis of Chronic Lymphocytic Leukemia (ASH 2022) - "In addition, we performed a combination of ibrutinib with PF8380, which showed a further decrease in cell viability and showed better anti-CLL effects.Conclusion Taken together, the present work provides evidence that the identified metabolic biomarkers can be used for CLL diagnosis and screening. Besides, this study was the first investigation on the role of ENPP2 in CLL. ENPP2 expression was increased in CLL cells, and the ENPP2 inhibitor PF-8380 inhibited cell proliferation and induced apoptosis, with therapeutic potential."

Chronic Lymphocytic Leukemia • CNS Disorders • Depression • Hematological Disorders • Hematological Malignancies • Leukemia • Metabolic Disorders • Oncology • Psychiatry • ANXA5

Inhibition of Autotaxin Ameliorates LPA-Mediated Neuroinflammation and Alleviates Neurological Dysfunction in Acute Hepatic Encephalopathy. (PubMed, ACS Chem Neurosci) - "We demonstrate that the autotaxin (ATX) inhibitor PF-8380 attenuates neuroinflammation and improves neurological dysfunction in the mouse model of HE...The neurobehavioral symptoms for HE such as the cognitive and motor function deficit and overall clinical grading score were significantly improved in ATXi-treated mice. Mouse astrocytes and microglia stimulated with NHCL with or without ATXi showed significant attenuation of oxidative stress and the neuroinflammatory effect of NH4CL in ATXi-treated cells."

Journal • CNS Disorders • Hepatic Encephalopathy • Hepatology • Immunology • Inflammation • Liver Failure • Oncology • IL1B • IL6 • TNFA

A type IV Autotaxin inhibitor ameliorates acute liver injury and nonalcoholic steatohepatitis. (PubMed, EMBO Mol Med) - "Then, we evaluated the effects of Cpd17, in comparison with the classic type I inhibitor PF8380, in vitro, where Cpd17 showed higher efficacy...Finally, the therapeutic potential of Cpd17 was investigated in CCl -induced acute liver injury and diet-induced nonalcoholic steatohepatitis, demonstrating an excellent potential of Cpd17 in reducing liver injury in both disease models in vivo. We conclude that ATX inhibition, by type IV inhibitor in particular, has an excellent potential for clinical application in liver diseases."

Journal • Fibrosis • Hepatology • Immunology • Inflammation • Liver Failure • Non-alcoholic Steatohepatitis • RHOA

Hybrid imidazo[1,2-a]pyridine analogs as potent ATX inhibitors with concrete in vivo antifibrosis effect. (PubMed, Arch Pharm (Weinheim)) - "Herein, a series of imidazo[1,2-a]pyridine compounds (1-11) were designed as ATX inhibitors through a hybrid strategy by combining the imidazo[1,2-a]pyridine skeleton in GLPG1690 and the benzyl carbamate moiety in PF-8380. Accordingly, 19 was tested directly for in vivo antifibrotic effects through a bleomycin model (H&E staining), in which 19 effectively alleviated lung structural damage and fibrosis at an oral dose of 20 and 60 mg/kg. Collectively, 19 qualified as a promising ATX inhibitor for potential application in fibrosis-relevant disease treatment."

Journal • Preclinical • Fibrosis • Immunology

Design, synthesis and promising anti-tumor efficacy of novel imidazo[1,2-a]pyridine derivatives as potent autotaxin allosteric inhibitors. (PubMed, Eur J Med Chem) - "Aiming to track the potential antitumor effect of novel allosteric autotaxin (ATX) inhibitors, a hybrid strategy was utilized by merging ATX inhibitors PF-8380 and GLPG1690, while the piperazinyl group in GLPG1690 was replaced with benzene ring to furnish imidazo[1,2-a]pyridine derivatives 10ã10k. Meanwhile, 10c was capable of inducing weak to moderate apoptosis and achieved notable G2 phase arrest on RAW264.7 cells. Taken together, 10c may serve as a novel lead to probe possible role of ATX allosteric inhibitors in tumor diseases."

Journal • Oncology

Nucleotide pyrophosphatase/phosphodiesterases (NPPs) including NPP1 and NPP2/ ATX as important drug targets: A patent review (2015-2020). (PubMed, Expert Opin Ther Pat) - "In addition to IOA-289 which has passed Phase Ia clinical trials; potent ATX inhibitor compounds such as BLD-0409, IPF and BBT-877 have been placed in phase I clinical studies. Some of the most promising ATX inhibitors in recent years are closely related analogs of previously known inhibitors, such as PF-8380. Knowledge of the structure activity relationship of such promising inhibitors can potentially translate into the discovery of more potent and effective inhibitors of NPP with a variety of structural characteristics and favourable therapeutic activities."

Journal • Review • CNS Disorders • Dermatology • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Inflammation • Multiple Sclerosis • Oncology • Pruritus • Pulmonary Disease • Respiratory Diseases

A defective lysophosphatidic acid-autophagy axis increases miscarriage risk by restricting decidual macrophage residence. (PubMed, Autophagy) - "In therapeutic studies, supplementation with LPA or the autophagy inducer rapamycin significantly promotes dMφ autophagy and cell residence, and improves embryo resorption in Enpp2 and spontaneous abortion mouse models, which should be dependent on the activation of DDIT4-autophagy-CLDN7-adhesion molecules axis. This observation reveals that inactivation of ENPP2-LPA metabolism and insufficient autophagy of dMφ result in resident obstacle of dMφ and further increase the risk of spontaneous abortion, and provides potential therapeutic strategies to prevent spontaneous abortion.Abbreviations: ACTB: actin beta; ADGRE1/F4/80: adhesion G protein-coupled receptor E1; Atg5: autophagy related 5; ATG13: autophagy related 13; BECN1: beclin 1; CDH1/E-cadherin: cadherin 1; CDH5/VE-cadherin: cadherin 5; CFSE: carboxyfluorescein succinimidyl ester; CLDN7: claudin 7; CSF1/M-CSF: colony stimulating factor 1; CSF2/GM-CSF: colony stimulating factor 2; Ctrl: control; CXCL10/IP-10:..."

Journal • Metabolic Disorders • ATG5 • BECN1 • CD61 • CDH1 • CDH5 • CSF2 • CXCL10 • DDIT4 • FGF2 • GAPDH • HIF1A • HNF1A • ITGAM • KLRB1 • KRT7 • LPL • LYZ • MAP1LC3B • MRC1 • PPARG • PTPRC • RHEB • SQSTM1 • TJP1 • VCAM1

Novel imidazo[1,2-a]pyridine derivatives as potent ATX allosteric inhibitors: Design, synthesis and promising in vivo anti-fibrotic efficacy in mice lung model. (PubMed, Bioorg Chem) - "Aiming to develop novel allosteric autotaxin (ATX) inhibitors, hybrid strategy was utilized by assembling the benzyl carbamate fragment in PF-8380 onto the imidazo[1,2-a]pyridine skeleton of GLPG-1690...Subsequently, 13c was forwarded into an in vivo bleomycin-induced mice lung fibrosis model...Except for the fundamental H-bond and π-π interactions, an extra H-bond between the 1,3-benzodioxole (O atom) and Phe306 offered great rationale in constraining the binding conformation of 13c. Finally, binding free energy calculation was conducted to assist in the efficient identification of allosteric ATX inhibitors."

Journal • Preclinical • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Respiratory Diseases

Targeting autotaxin impacts disease advance in the SOD1-G93A mouse model of amyotrophic lateral sclerosis. (PubMed, Brain Pathol) - "We show here that PF-8380, a specific ATX inhibitor, reduced intrinsic membrane excitability (IME) of hypoglossal MNs in brainstem slices, supporting that baseline ATX activity regulates MN IME...These outcomes support that neuroprotective effects of interfering with ATX in SOD1-G93A mice rely, at least in part, on LPA  knockdown in MNs. Therefore, we propose ATX as a potential target and/or a biomarker in ALS and highlight ATX inhibitors as reasonable tools with therapeutic usefulness for this lethal pathology."

Journal • Preclinical • Amyotrophic Lateral Sclerosis • CNS Disorders

Disrupted Blood-Brain Barrier and Mitochondrial Impairment by Autotaxin-Lysophosphatidic Acid Axis in Postischemic Stroke. (PubMed, J Am Heart Assoc) - "Treatment with autotaxin inhibitors (HA130 or PF8380) or autotaxin/LPA receptor inhibitor (BrP-LPA) rescued endothelial permeability and mitochondrial dysfunction in I/R group. Conclusions Autotaxin-LPA signaling blockade attenuates blood-brain barrier disruption and mitochondrial function following I/R, suggesting targeting this axis could be a new therapeutic approach toward treating ischemic stroke."

Journal • Cardiovascular • Cerebral Hemorrhage • Hematological Disorders • Ischemic stroke • Metabolic Disorders

Inhibition of Autotaxin and Lysophosphatidic Acid Receptor 5 Attenuates Neuroinflammation in LPS-Activated BV-2 Microglia and a Mouse Endotoxemia Model. (PubMed, Int J Mol Sci) - "In terms of the communication between systemic inflammation and neuroinflammation, both inhibitors significantly attenuated LPS-mediated systemic TNFα and IL-6 synthesis, while IL-1β was only reduced by PF8380. Inhibition of ATX and LPA5 may thus provide an opportunity to protect the brain from the toxic effects that are provoked by systemic endotoxemia."

Journal • Preclinical • Immunology • Inflammation • GFAP • IL1B • IL6 • JUN • RELA • STAT1 • TLR4 • TNFA

Crystalline silica particles induce DNA damage in respiratory epithelium by ATX secretion and Rac1 activation. (PubMed, Biochem Biophys Res Commun) - "Using 16HBE human bronchial epithelial cells, we show ATX secretion at 3 min, and that ATX inhibitors (HA130 and PF8380) prevented both CSi-induced mitochondrial depolarization and DNA damage (detected by γH2AX and Comet assay analysis)...Furthermore, Rac1 was activated at 3 min, and a Rac1 inhibitor (NSC23766) prevented mitochondrial depolarization and genotoxicity...Our data indicate that CSi rapidly activate the ATX-LPA axis and within minutes this leads to DNA damage in bronchial epithelial cells. Thus, ATX mediates very rapid DNA damaging effects of inhaled particles."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Oncology • Respiratory Diseases • RAC1 • TP53BP1

An updated patent review of autotaxin inhibitors (2017-present). (PubMed, Expert Opin Ther Pat) - "In addition to GLPG1690 currently in phase III clinical studies for IPF, BBT-877 and BLD-0409 as potent ATX inhibitors have been enrolled in phase Ⅰ clinical evaluation, meanwhile, many effective molecules were also reported successively. However, most emerging ATX inhibitors in the last four years are closely analogs of previous entities, such as GLPG1690 and PF-8380, which translate into the urgently identification of ATX inhibitors with diverse structural features and promising properties in the near future."

Journal • Review • CNS Disorders • Dermatology • Fibrosis • Immunology • Inflammation • Metabolic Disorders • Multiple Sclerosis • Oncology • Pruritus

Autotaxin in ascites promotes peritoneal dissemination in pancreatic cancer. (PubMed, Cancer Sci) - "An in vitro study using two PDAC cell lines, AsPC-1 and PANC-1, showed that ATX-LPA signaling promoted cancer cell migration via the activation of the downstream signaling, and this increased cell migration was suppressed by an ATX inhibitor, PF-8380...Moreover, there was a positive correlation between the amount of ATX in ascites and the degree of disseminated cancer progression. These findings demonstrated that ATX in ascites works as a promotor of peritoneal dissemination, and the targeting of ATX must represent a useful and novel therapy for peritoneal dissemination of PDAC."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Autotaxin inhibition reduces cardiac inflammation and mitigates adverse cardiac remodeling after myocardial infarction. (PubMed, J Mol Cell Cardiol) - "ATX/LPA signaling nexus plays an important role in modulating inflammation after AMI and targeting this mechanism represents a novel therapeutic target for patients presenting with acute myocardial injury."

Journal • Atherosclerosis • Cardiovascular • Congestive Heart Failure • Dyslipidemia • Heart Failure • Immunology • Inflammation • Myocardial Infarction

Autotaxin/lysophosphatidic acid signaling mediates obesity-related cardiomyopathy in mice and human subjects. (PubMed, J Cell Mol Med) - "Administration with autotaxin inhibitor, PF-8380 effectively attenuates high fat diet-induced cardiac hypertrophy, dysfunction and inflammatory response...More importantly, circulating levels of autotaxin are positively correlated with cardiac dysfunction and hypertrophy in 55 patients. In conclusion, present study uncovers the correlation between circulating autotaxin and cardiac parameters in mice and human patient, and provided solid evidence of the therapeutic application of autotaxin inhibitor in combating obesity-related cardiomyopathy."

Journal • Cardiomyopathy • Cardiovascular • Genetic Disorders • Immunology • Obesity