PF-8380 / Pfizer - LARVOL DELTA

Autotaxin/Lysophosphatidic Acid Axis Promotes Periodontitis by Modulating Macrophage Osteoclastogenesis and Inflammation. (PubMed, J Clin Periodontol) - "The ATX/LPA axis plays a significant regulatory role in osteoclastogenesis and osteoclast activity and may enable selective control of bone loss and inflammation in periodontitis. Therefore, targeting ATX inhibition may represent a novel therapeutic strategy for preventing alveolar bone resorption and periodontal inflammation in patients with periodontitis."

Journal • Dental Disorders • Inflammation • Osteoporosis • Periodontitis • TRAP

Lysophosphatidic acid drives to mirror-image pain via corpus callosum-mediated propagation of inflammatory responses. (PubMed, Commun Biol) - "Furthermore, PF8380 or minocycline suppressed bilateral hyperalgesia with MIP, supporting the therapeutic relevance of targeting LPA signalling and microglial activation. Because dysregulated LPA signalling and microglial activation are features of other neuroinflammatory conditions, transcallosal glial crosstalk may also contribute to widespread pain syndromes. Our findings highlight the therapeutic potential of targeting LPA-related pathways."

Journal • Inflammation • Musculoskeletal Pain • Pain

Autotaxin Induces S1P/S1PR1 Signaling to Affect Th17/Treg Cell Balance and Exacerbate Intestinal Inflammation in Colitis. (PubMed, Int J Mol Sci) - "ATX inhibitor PF8380 treatment led to reduced levels of S1P/S1PRs in colitic mice. Consistent with this, the S1PR antagonist etrasimod was able to alleviate ATX-induced intestinal inflammation, as well as partially restore ATX-induced Th17/Treg imbalance in MLNs and the spleen...Furthermore, S1PR1 mediates the effect of ATX on Th17/Treg cell differentiation and function in vivo. Therefore, ATX affects the differentiation and function of Th17/Treg cells through S1P/S1PR1 signaling, increased ATX expression leading to Th17/Treg cell imbalance, intestinal mucosal immune dysfunction, and exacerbating intestinal inflammation."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • S1PR1

IOA-244, a novel p110δ PI3K inhibitor, blocks breast tumour progression on either mono- or combined-therapy. (PubMed, Cell Death Discov) - "Full tumour control, however, was achieved when IOA-244 used in a combinatorial regimen with the PF-8380 ATX inhibitor. In agreement with the mouse model, the amount of CD163+/CD204+macrophages and ATX were much higher in grade III human breast carcinomas compared to grade I. Our work provides the first in vivo preclinical evidence showing that IOA-244 is a potential highly effective drug for breast cancer treatment and depending on the phase of the tumour can be used either as a single agent or as a combinatorial regimen."

Journal • Breast Cancer • Oncology • Solid Tumor • CD163 • MSR1

Targeting the Endothelial Autotaxin-LPA-LPP3 Axis Mitigates Blood-Brain Barrier Disruption and Mitochondrial Dysfunction After Ischemic Stroke (Neuroscience 2025) - "Inhibition of ATX (HA130, PF8380) or LPA receptors (BrP-LPA, Ki16425, AM095) significantly reversed these effects, restoring BBB integrity and mitochondrial function...Collectively, our results identify the endothelial ATX-LPA-LPP3 axis as a central regulator of vascular permeability and mitochondrial integrity after stroke. Targeting this pathway may offer a novel therapeutic strategy to protect the BBB and improve functional outcomes during reperfusion therapy."

CNS Disorders

Spatial T1-Mapping of Cardiac Fibrosis Identifies Causal Protein Drivers through Deep Learning and Mendelian Randomization (AHA 2025) - "eQTL SMR identified LMF1 (p=8.3×10-5), JMJD6 (p=1.7×10-4), RIT1 (p=3.96×10-4). Targets with existing inhibitors include CTSS (VBY-036, RO5459072), PDE5A (sildenafil, tadalafil), and ENPP2 (ONO-8430506, PF-8380, IOA-289).Conclusions AI-derived spatial fibrosis phenotypes using VAE decomposition of T1 maps reveal hidden prognostic information and region-specific biological drivers invisible to conventional mean T1 analysis, identifying causal protein targets (FOLH1, ENPP2, CTSS, PDE5A) amenable to existing inhibitors for precision anti-fibrotic therapies."

Cardiovascular • Congestive Heart Failure • Coronary Artery Disease • Fibrosis • Heart Failure • Immunology • CTSS • DLG2 • ENPP2 • FABP4 • FOLH1 • LEP • PDE5A • RIT1 • TMPRSS6 • TNFRSF1A

Rational design and identification of potent imidazole-fused Autotaxin inhibitors for treatment of idiopathic pulmonary fibrosis. (PubMed, Eur J Med Chem) - "Herein, in pursuit of expanding the chemical space of novel ATX inhibitors, a series of imidazole-fused (imidazo[1,2-b]pyridazine and benzo[d]imidazole) derivatives with aliphatic amine linkers were designed through integrating the structural features of GLPG-1690 and PF-8380. Significantly, in the Bleomycin-induced pulmonary fibrosis mouse model, 12 has certainly reduced collagen deposition and ameliorated lung fibrosis. Overall, compound 12 turned out to be a well-characterized potent ATX inhibitor warranting further investigation for the treatment of idiopathic pulmonary fibrosis."

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

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