PF-543 / Pfizer - LARVOL DELTA

Compound Gardenia Radix Granule mitigates liver fibrosis in CCl4-induced mice by repressing SphK1-S1PR2 axis-mediated p-ERK signaling. (PubMed, Phytomedicine) - "CGRG ameliorates LF by inhibiting the SphK1-S1PR2-ERK pathway, offering new mechanistic insights and supporting its clinical application. These findings highlight the value of TCM polypharmacology in targeting redundant fibrogenic pathways."

Journal • Preclinical • Fibrosis • Immunology • Liver Cirrhosis • Metabolic Disorders • COL1A1 • IL1B • S1PR2 • SPHK1 • TGFB1 • TNFA

Autophagy-dependent secretion of ENO1 mediates chemoresistance of glioblastoma and tumor microenvironment remodeling. (PubMed, Cell Death Dis) - "In this study, we demonstrated that temozolomide (TMZ) could activate the autophagy-dependent secretory pathway to promote extracellular secretion of Alpha-enolase (ENO1)...Importantly, in vivo studies confirmed that combined therapy with the SPHK1 inhibitor PF-543, the TLR4 antagonist TAK-242, and TMZ synergistically suppressed tumor growth and significantly enhanced the efficacy of TMZ. Collectively, these findings reveal that ENO1 mediates intercellular crosstalk between GBM cells and M2-TAMs via autophagy-dependent secretion, thereby driving TMZ chemoresistance and functioning as an oncogene in GBM. Targeting the ENO1/TLR4 signaling axis reshapes the immune microenvironment and enhances the efficacy of TMZ, offering a promising therapeutic strategy and potential combinatorial targets for precision therapy in GBM."

Biomarker • IO biomarker • Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • ENO1 • SPHK1

SPHK1-mediated M2 macrophage polarization drives TGF-β1-dependent thrombus fibrosis. (PubMed, Front Immunol) - "This study demonstrates that SPHK1 promotes M2 macrophage polarization and drives TGF-β1-dependent thrombus fibrosis, underscoring its critical role in the progression of CTEPH. Pharmacological inhibition of SPHK1 by PF543 effectively attenuates fibrotic remodeling and suppresses M2 macrophage polarization, suggesting that SPHK1 may serve as a promising therapeutic target for the treatment of chronic thrombus-associated fibrosis."

Journal • Cardiovascular • Fibrosis • Hematological Disorders • Hypertension • Immunology • Pulmonary Arterial Hypertension • Pulmonary Disease • Pulmonary Embolism • Respiratory Diseases • Thrombosis • ARG1 • CD36 • CD68 • FASN • SCARB1 • SPHK1 • TGFB1

Mechanisms and potential therapeutic targets of SphK1 and SphK2 in hepatocellular carcinoma. (PubMed, Front Med (Lausanne)) - "It also maintains telomere activity via mitochondrial S1P, which promotes tumor survival and facilitates resistance to regorafenib. In targeted therapy, SphK1 inhibitors (e.g., PF-543) and SphK2 inhibitors (e.g., ABC294640) have shown significant anti-tumor effects in preclinical models...This paper systematically summarizes the mechanisms of action and therapeutic progress of SphK1/SphK2 in HCC. It provides an important theoretical basis for the clinical translation of precision therapy strategies in HCC."

Journal • Review • Hepatocellular Cancer • Oncology • Solid Tumor • SPHK1 • SPHK2

Structural dynamics of sphingosine kinase 1 regulation and inhibition. (PubMed, bioRxiv) - "We identify a previously uncharacterized catalytic intermediate with a distinct conformation and a highly dynamic lipid-binding loop 1 (LBL-1), sensitive to potent inhibitors such as PF-543...Our findings reveal a multilayered regulatory mechanism driven by structural flexibility and establish a novel inhibitory paradigm. This framework provides critical insight into SK1 regulation and a foundation for developing next-generation SK1-targeted therapeutics."

Journal • Oncology • SPHK1

A new insight into the mechanism of DEHP-induced cardiotoxicity: Triggering pyroptosis of cardiomyocytes by disrupting sphingolipid metabolism. (PubMed, J Hazard Mater) - "DEHP exposure also increased pyroptosis-related proteins, reversible via SPHK1 inhibitor PF543 or S1PR2 siRNA. In conclusion, this study first links DEHP-induced cardiac pyroptosis to SPHK1/S1PR2 signaling in mice, providing novel insights into DEHP-associated cardiotoxicity, contributing to cardiac damage and thereby offering new theoretical insights into DEHP-related cardiac toxicity."

Journal • Cardiovascular • Metabolic Disorders • CRP • S1PR2 • SPHK1

Investigate the potential inhibitors of sphingosine kinase 1 (SphK1) with molecular dynamics and artificial intelligence drug design methods. (PubMed, J Mol Model) - "Therefore, this study aims to investigate the interaction mechanism between Epidanshenspiroketallactone, PF-543, and SPHK1 in the J-type channel, and to design new small molecules using AI Drug Design (AIDD)...The MD simulation force field was selected as the AMBER99SB force field, the temperature was set at 310 K, and the total MD simulation time was 7.2 μs. A recurrent neural network-long short-term memory (RNN-LSTM) machine model was employed for the design of novel inhibitors."

Journal • SPHK1

Alisol A 24-acetate protects against NASH-associated fibrosis via suppression of Kupffer cell-derived SPHK1/S1P axis. (PubMed, Phytomedicine) - "AA exerts potent anti-steatotic, anti-inflammatory, and antifibrotic effects in experimental NASH, primarily by targeting the SPHK1/S1P signaling axis in Kupffer cells. This study is the first to identify AA as a direct modulator of KC-derived SPHK1 signaling, offering a novel strategy to disrupt KC-HSC crosstalk and mitigate liver fibrosis in NASH."

Journal • Fibrosis • Hepatocellular Cancer • Hepatology • Immunology • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Oncology • Solid Tumor • IL1B • SPHK1 • TNFA

Hot on the TRAIL: Targeting SPHK1 in Colorectal Cancer: Therapeutic Potential of PF-543. (PubMed, Dig Dis Sci) - No abstract available

Journal • Colorectal Cancer • Oncology • Solid Tumor • SPHK1

High-throughput split-GFP antiviral screening assay against fusogenic paramyxoviruses. (PubMed, Antiviral Res) - "Two molecules were identified: Cathepsin Inhibitor 1 with henipavirus-specific activity and PF-543 with pan-paramyxovirus activity. Both molecules inhibit viral replication by blocking cell-cell fusion. The split-GFP assay presented here will enable the development of extensive drug discovery initiatives aimed at identifying much-needed pan-henipavirus/paramyxovirus inhibitors."

Journal • Infectious Disease • Measles • Mumps

Sphingolipid modulation and anti-tumor activity of Jaspine B in HepG2 bearing mice. (PubMed, Arch Pharm Res) - "The anti-cancer effect and reduced plasma S1P levels induced by Jaspine B were comparable to PF543, a selective SphK1 inhibitor, in HepG2-xenografted mice. In conclusion, this study provides in vitro and in vivo evidence that Jaspine B is a promising anti-cancer agent for hepatocellular carcinoma, acting through SphK1 inhibition, with favorable pharmacokinetic and tumor distribution properties. This study also suggested that reduced plasma S1P levels may serve as a therapeutic biomarker for SphK1 inhibitors in hepatocellular carcinoma treatment."

Journal • Preclinical • Hepatocellular Cancer • Oncology • Solid Tumor • SPHK1

FAM46C expression sensitizes multiple myeloma cells to PF-543-induced cytotoxicity (EACR 2025) - "Overall, our findings indicate that FAM46C plays a crucial role in drug response, enhancing sensitivity to PF-543 in both in vitro and in vivo settings. Our results reveal a novel synergistic interaction between FAM46C expression and SPHK1 inhibition, presenting a promising therapeutic approach for MM treatment."

Hematological Malignancies • Multiple Myeloma • Oncology • SPHK1 • SPHK2 • TENT5C

Machine learning framework coupled with CADD for predicting sphingosine kinase 1 inhibitors. (PubMed, Comput Biol Med) - "MM/GBSA calculations showed that PF-543 had the lowest predicted binding energy (-101.25 kcal/mol), followed by IS01265 (-94.52 kcal/mol), IS01027 (-85.53 kcal/mol), and IS00998 (-82.57 kcal/mol), indicating their strong binding affinity to the protein...All four top-ranked ligands displayed strong predicted drug-like characteristics, such as high gastrointestinal absorption, and moderate oral bioavailability, with IS00998 standing out for its excellent solubility. Our integrated approach, combining machine learning, molecular docking, and molecular dynamics simulations, highlights the potential of computational methods to accelerate the discovery of SphK1 inhibitors, offering valuable insights for therapeutic innovation."

Journal • Cardiovascular • Oncology • SPHK1

The Combination of PF-543 and TRAIL Effectively Induces Apoptotic Cell Death and Inhibits Stem Cell-Like Properties Through the SPHK1/S1PR1/STAT3 Pathway in TRAIL-Resistant Colorectal Cancer Cells. (PubMed, Dig Dis Sci) - "We identified the molecular mechanisms underlying acquired TRAIL resistance in CRC cells and suggest that targeting SPHK1 represents a potential strategy to overcome TRAIL resistance and inhibit CRC metastasis."

Journal • Colorectal Cancer • Oncology • Solid Tumor • S1PR1 • SPHK1 • TNFRSF10C

FAM46C Expression Sensitizes Multiple Myeloma Cells to PF-543-Induced Cytotoxicity. (PubMed, Biomolecules) - "Using an in vivo xenograft model, we further validated these findings, showing that FAM46C-expressing MM tumors are indeed sensitive to PF-543 while tumors harboring the D90G loss-of-function variant of FAM46C are not. Overall, our results uncover a novel synergistic interaction between FAM46C expression and SphK1 inhibition, highlighting a promising therapeutic strategy for MM treatment."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology • SPHK1 • SPHK2 • TENT5C

Structural dynamics of sphingosine kinase 1 regulation and inhibition. (PubMed, Res Sq) - "We identify a previously uncharacterized catalytic intermediate featuring a distinct conformation with a highly dynamic lipid-binding loop 1 (LBL-1), sensitive to potent inhibitors such as PF-543...Notably, SK1 forms functionally distinct dimers stabilized by ligand or membrane interactions, revealing a dynamic, multilayered regulatory mechanism governed by structural flexibility. These findings define a novel inhibitory mechanism and offer a structural framework for developing next-generation SK1-targeted therapeutics."

Journal • Oncology • SPHK1

Discovery of Sphingosine Kinase Inhibition by Modified Quinoline-5,8-Diones. (PubMed, Pharmaceuticals (Basel)) - "SphK inhibition has been an attractive target for anticancer drug development for the past decade, with SphK inhibitors such as PF-543 and opaganib exhibiting clinical antitumour effects. Molecular modelling on the pyrrolidine quinoline-5,8-dione construct revealed favourable docking, low binding energies and opportunities for further improvement. Although the screening of anticancer activity was inconclusive, low micromolar dual SphK1/2 inhibition with the quinoline-5,8-dione framework has been identified for the first time, and a plausible new binding mode has been identified."

Journal • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • SPHK1 • SPHK2

SPHK1 enhances olaparib resistance in ovarian cancer through the NFκB/NRF2/ferroptosis pathway. (PubMed, Cell Death Discov) - "Functionally, NF-κB p65 attenuated the PF-543-induced ferroptosis, and this effect was rescued by ferroptosis inducer erastin and RSL3. In vivo experiments also confirmed that the SPHK1 inhibitor increased olaparib sensitivity. A combination of SPHK1 inhibitors and olaparib may provide a therapeutic strategy for ovarian cancer."

Journal • Oncology • Ovarian Cancer • Solid Tumor • NFKBIA • SPHK1

The suppression of the SPHK1/S1P/S1PR3 signaling pathway diminishes EGFR activation and increases the sensitivity of non-small cell lung cancer to gefitinib. (PubMed, Curr Res Pharmacol Drug Discov) - "Utilizing SPHK1/S1P/S1PR3 inhibitors, namely PF543, TY52156, and FTY720, we established that the SPHK1/S1P/S1PR3 axis modulates EGFR activation in NSCLC. These genes were predominantly associated with pathways such as axon guidance, microRNAs in cancer, and the JAK-STAT signaling pathway, among others. Overall, targeting the SPHK1/S1P/S1PR3 signaling pathway represents a promising therapeutic strategy to enhance gefitinib sensitivity in NSCLC."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • SPHK1

Sphingosine kinase 1 inhibition aggravates vascular smooth muscle cell calcification. (PubMed, Pflugers Arch) - "Similarly, the SPHK1 inhibitor PF-543 and SPHK1 knockdown up-regulated osteogenic signaling in VSMCs and aggravated VSMC calcification...In conclusion, SPHK1 inhibition, knockdown, or deficiency aggravates vascular pro-calcific signaling and calcification. The reduced calcification after inhibition of S1P export suggests a possible involvement of intracellular S1P, but further studies are required to elucidate the complex roles of SPHKs and S1P signaling in calcifying VSMCs."

Journal • Chronic Kidney Disease • Metabolic Disorders • Nephrology • Renal Disease • SPHK1

Sexual dimorphism in right ventricular adaptation to pressure overload involves differential angiogenic response. (PubMed, Am J Physiol Heart Circ Physiol) - "Furthermore, effect of estradiol on RVEC was inhibited by Sphk1 inhibitor (PF-543). Together, female Fischer CDF rats develop adaptive RV remodeling post-PAB compared to mal-adaptive remodeling in male rats. Moreover, the adaptive remodeling in female rats is associated with better RV angiogenic response that may result from better angiogenic ability of female RVEC and proangiogenic effects of estradiol through Sphk1."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • SPHK1

Sphk1/S1P pathway promotes blood-brain barrier breakdown after intracerebral hemorrhage through inducing Nlrp3-mediated endothelial cell pyroptosis. (PubMed, Cell Death Dis) - "The Sphk1 inhibitor PF543 and siRNAs were utilized to explore the pathway's impact on BBB integrity and the underlying mechanisms...Furthermore, mechanistic studies reveal that Sphk1 promotes Nlrp3-mediated pyroptosis of brain endothelial cells through the ERK1/2 signaling pathway. Taken together, the Sphk1/S1P pathway plays a critical role in ICH-induced BBB breakdown, and its inhibition represents a promising therapeutic strategy for ICH management."

Journal • Cardiovascular • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • Vascular Neurology • NLRP3 • SPHK1

Targeting SphK1/S1PR3 axis ameliorates sepsis-induced multiple organ injury via orchestration of macrophage polarization and glycolysis. (PubMed, Biochim Biophys Acta Mol Cell Res) - "Intriguingly, S1PR3 knockdown proficiently dampened glycolysis-associated markers, retrieved LPS-modulated M1/M2 polarization and attenuated NF-κB p65 activation. In conclusion, our study provides the first evidence that PF-543 orchestrates proportional imbalance of macrophage polarization and the Warburg effect in a SphK1/S1PR3 dependent manner during sepsis, mitigating both hyperinflammation and multi-organ failure, adding a novel puzzle piece to pharmacologically exploitable therapy for sepsis."

Journal • Infectious Disease • Inflammation • Septic Shock • HIF1A • PFKFB3 • SPHK1

Sphingosine-1-phosphate alleviates Sjögren's syndrome-like symptoms via inducing autophagy and regulating status of Treg cells in NOD mice. (PubMed, Int Immunopharmacol) - "S1P therapy alleviated SS-like symptoms in NOD mice by increasing the number of Treg cells, by restoring Treg cell function, and by positively regulating autophagy via crosstalk. Such therapy may be a new and valuable SS treatment option."

Journal • Preclinical • Immunology • Obesity • Sjogren's Syndrome • FOXP3 • S1PR1 • SPHK1

TARGETING SPHINGOSINE 1-PHOSPHATE SIGNALING TO AMELIORATE HEPATIC INJURY IN WILSON DISEASE (AASLD 2024) - "Two drugs were separately used to block S1P signaling in vivo: sphingosine Kinase 1 specific inhibitor PF543 (3mg/kg/d), or FTY720 (1mg/kg/d), an agonist which causes S1P receptor internalization. Our findings indicate that copper overload could remodel the sphingolipid metabolism of the liver. The blockade of S1P signaling could improve liver damage in WD mice."

Fibrosis • Genetic Disorders • Hepatology • Immunology • Inflammation • Liver Failure • Metabolic Disorders • Movement Disorders • ATP7B • SPHK1