S1PR agonist / Boehringer Ingelheim, Exelixis - LARVOL DELTA

Sphingosine-1-phosphate receptor modulators overcome FLT3 inhibitor resistance in Acute Myeloid Leukemia with FLT3-ITD and NRAS mutations through sphingosine kinase 1/AKT pathway downregulation. (ASH 2025) - "SphK1 is linked toFLT3 inhibitor resistance, as prolonged sorafenib exposure was shown to activate the Sphk1/S1P axis.Here we studied the efficacy of targeting Sphk1 with sphingosine-1-phosphate receptor (S1PR)modulators in conjunction with FLT3 inhibitors to overcome FLT3 inhibitor resistance mediated by NRASmutations in AML cells with FLT3-ITD. MethodsMOLM-14 and MV4-11 human FLT3-ITD AML cell lines with NRAS mutations including G12D, G12S, G12C,Q61K and Q61H and FLT3-ITD AML patient blasts with G13V and G13D mutations were cultured with theFLT3 inhibitors gilteritinib (10 nM) or quizartinib (1 nM) and/or the S1PR modulators fingolimod (FTY720; 2.5 μM) or mocravimod (KRP203; 5 μM)...ConclusionsThe S1PR agonists fingolimod (FTY720) and mocravimod (KRP203) resensitize FLT3-ITD AML cellsharboring G12D, G12S, Q61K, and Q61H, but not G12C, NRAS mutations to FLT3 inhibitors. The datasupport potential clinical efficacy of combination regimens with these clinically applicable..."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • ANXA5 • BAD • FLT3 • NRAS • SPHK1 • STAT5

Preventing light-induced toxicity in a new mouse model of sector retinitis pigmentosa caused by Rhodopsin M39R variant. (PubMed, Cell Death Discov) - "Transcriptomic analysis in RhoM39R/M39R KI mice revealed upregulation of Sphingosine 1-P Receptor (S1pr) transcripts. Treatment with the S1PR agonist Fingolimod (FTY720) before bright light exposure significantly reduced degeneration, demonstrating a protective effect in both heterozygous and homozygous models and suggesting potential as a therapeutic approach for sector RP patients."

Journal • Preclinical • Genetic Disorders • Inherited Retinal Dystrophy • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa

Coupling of a free energy perturbation method with GROMACS molecular dynamics to probe the effect of mutations on ligand binding: towards the design of selective S1PR agonists and antagonists (ACS-Fall 2025) - "In addition, we computed free energy changes for each wild type and mutant complex and have correlated these computational predictions with experimental binding and activation results. We will present data that allows one to use this methodology to computationally design high affinity lead compounds that exhibit receptor subtype selectivity."

SPHK1

Multimodal Analysis of IBD Patients Coupled with Machine Learning Identifies Immunometabolism Targets for Potential Therapies (FOCIS 2025) - "From our results we identified SPHK1, a sphingosine kinase which belongs to the clinically validated sphingolipid pathway, as novel therapeutic target for UC and CD and differentiated it from S1PR agonists, in silico as well as experimentally. This work highlights the added value of multi-modal analysis to dissect this complex disease and paves the way to the discovery of novel therapeutic opportunities in IBD."

Clinical • Machine learning • Crohn's disease • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • SPHK1

Intracellular Sphingosine-1-Phosphate Induces Lipolysis Through Direct Activation of Protein Kinase C Zeta. (PubMed, FASEB J) - "Here, we have concentrated on the latter, as 10-50 μM S1P potently increased lipolysis in differentiated 3T3-L1 adipocytes, whereas S1P concentrations sufficient to activate S1P receptors (S1PRs; 0.1-1 μM) or S1PR agonists had no effect...PKC zeta phosphorylation and activity, as well as HSL Ser660 phosphorylation, were increased in gWAT of DOP-treated mice. This study assigns lipolysis as the first physiological function of PKC zeta activation by S1P and identifies an exclusive adipocyte-specific aspect of S1P function in obesity."

Journal • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus • PRKCH

3D tissue-level analysis of intestinal T cell dynamics reveals dual effects of etrasimod on recruitment and tissue exit in experimental colitis (ECCO-IBD 2025) - "Moreover, while S1PR-dependent mechanisms regulate T cell egress from the gut, it remains unclear whether S1PR agonists modulate this process. Beyond reducing lymphocyte recruitment, etrasimod appears to create a tissue exit block, effectively trapping T cells within the intestinal compartment. These findings raise important questions about how enforced tissue residency influences local inflammatory circuits and may guide optimization of therapeutic strategies."

Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

Effects of Sphingosine-1-Phosphate on the Facilitation of Peripheral Nerve Regeneration. (PubMed, Cureus) - "In this research, six-week-old male Sprague-Dawley rats (total n=18) underwent transection of the inferior alveolar nerve (IAN) and were divided into three groups: S1PR agonist (FTY720) (n=6), saline control (n=6), and S1P1R antagonist (n=6). Additionally, the combination with S1P1R antagonists inhibited the effects of the agonists, further confirming the potential role of S1P1R in nerve repair. Our results suggest that mediating S1P1R signaling could facilitate the regeneration of peripheral nerves after injury."

Journal • Inflammation

Sphingosine-1-Phosphate Receptor 1 (S1P1) Agonist, Vibozilimod (BS6.890C), Effect on Bradycardia, Preclinical to First-in-human Clinical Translation (EADV 2024) - "Vibozilimod (VBZ, BS6.890C) is a novel S1PR agonist that acts on S1P1R and S1P5R while antagonizing S1P4R with significant lack of activity towards S1P3R...Materials & VBZ, etrasimod, ozanimod and siponimod were administered intravenously at a dose of 3 mg/kg in anesthetized male Sprague-Dawley rats and their effects on heart rate (HR) and mean arterial blood pressure (MAP) were studied... VBZ, a differentiated agonist at S1P1 and S1P5 receptors produced only a transient and well manageable effect on heart rate in humans, with faster recovery as observed in the preclinical model. Thus, the effects of VBZ observed in animal studies were successfully translated in humans in terms of reduction in magnitude of heart rate in Phase I study, thus providing improved safety on cardiac function."

P1 data • Preclinical • Anesthesia • Cardiovascular • Immunology • Inflammation • Macular Edema • Ophthalmology • S1PR1

Mitochondrial effects of S1P receptor agonists: when blocking lymphocyte egress is not the whole picture (ECTRIMS 2024) - "Introduction: Fingolimod (FTY720), an analog of sphingo-sine-1-phosphate (S1P) that inhibits the egress of lymphocytes through the internalization of S1P receptors, is a non-selective S1PR agonist that induces sustained lymphopenia and accumulates in the CNS...Objectives/Aims: We aimed to compare the putatively inactive form with the phosphorylated compound and with other analogs (Siponimod and Ponesimod), as they bind to distinct S1P receptors and their effects may not be specific of a single subtype... The identification of the altered mitochondrial mechanisms underpinning these therapeutic drugs might be of remarkable relevance to MS."

Metabolic Disorders • MFN2 • PFKFB3

Re-emergence of T lymphocyte-mediated synaptopathy in progressive multiple sclerosis. (PubMed, Front Immunol) - "Homologous chimeric experiments were executed incubating EAE mice T cells with siponimod and specific S1PR agonists or antagonists to identify the receptor involved in siponimod-mediated synaptic recovery. Transition from RRMS to SPMS involves the reappearance of T cell-mediated synaptotoxicity. Siponimod counteracts T cell-induced excitotoxicity, emphasizing the significance of inflammatory synaptopathy in progressive MS and its potential as a promising pharmacological target."

Journal • CNS Disorders • Inflammation • Multiple Sclerosis

1-Phosphate receptor agonists: A promising therapeutic avenue for ischemia-reperfusion injury management. (PubMed, Int Immunopharmacol) - "Notably, preconditioning and postconditioning strategies involving S1PR agonists like FTY720 have demonstrated efficacy in mitigating IRI. Despite this progress, comprehensive reviews delineating the therapeutic landscape of S1PR agonists in IRI remain limited. This review aspires to meticulously elucidate the protective roles and mechanisms of S1PR agonists in preventing and managing IRI affecting various organs, including the heart, kidney, liver, lungs, intestines, and brain, to foster novel pharmacological approaches in clinical settings."

Journal • Review • Cardiovascular • Reperfusion Injury • S1PR1

Managing Risks with Newer Oral Small Molecules in Patients with Inflammatory Bowel Diseases. (PubMed, Curr Gastroenterol Rep) - "Therefore, oral agents with greater selectivity in JAK inhibition, such as tofacitinib and upadacitinib, were later developed. Ozanimod and etrasimod, S1PR agonists, require closer safety profile monitoring by clinicians...However, they have been associated with AEs, and some require close monitoring prior to and during therapy. Clinicians should highlight these adverse events to patients while reassuring the safety profile of these novel SMDs for IBD is favorable."

Journal • Review • Cardiovascular • Gastroenterology • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammation • Inflammatory Bowel Disease

Emerging Oral Therapies for the Treatment of Psoriasis: A Review of Pipeline Agents. (PubMed, Pharmaceutics) - "Small molecules under development include tumor necrosis factor inhibitors, IL-23 inhibitors, IL-17 inhibitors, phosphodiesterase-4 inhibitors, Janus kinase inhibitors, A3 adenosine receptor agonists, and sphingosine-1-phosphate receptor 1 agonists, several of which are entering phase III trials. Oral microbials have also demonstrated success in early phase studies. As new oral therapies emerge for the treatment of psoriasis, real-world data and comparative trials are needed to better inform their use among patients."

Journal • Review • Dermatology • Immunology • Oncology • Psoriasis • IL17A • IL23A • S1PR1

Exploration of Tetrahydroisoquinoline- and Benzo[c]azepine-Based Sphingosine 1-Phosphate Receptor 1 Agonists for the Treatment of Multiple Sclerosis. (PubMed, J Med Chem) - "Because of the wide use of Fingolimod for the treatment of multiple sclerosis (MS) and its cardiovascular side effects such as bradycardia, second-generation sphingosine 1-phosphate receptor 1 (S1P1) agonist drugs for MS have been developed and approved by FDA. Furthermore, in vivo efficacy of our compounds was clearly demonstrated with PLC and EAE studies. Also, the preliminary in vitro cardiovascular safety of our compound was verified with human iPSC-derived cardiomyocytes."

Journal • Cardiovascular • CNS Disorders • Multiple Sclerosis • S1PR1

Rational design of S1Pr3-selective agonists as novel antifungal agents (ACS-Fall 2023) - "We will present here our computer-aided drug design (CADD) of S1Pr3-selective agonists based on CYM5541 and FTY720. The binding dynamics of several known S1Pr agonists and antagonists in an investigation into the root of S1Pr selectivity will also be discussed."

CNS Disorders • Immune Modulation • Infectious Disease • Multiple Sclerosis • S1PR1

S1PR1 serves as a viable drug target against pulmonary fibrosis by increasing the integrity of the endothelial barrier of the lung. (PubMed, Acta Pharm Sin B) - "Selective activation of S1PR1 with an S1PR1 agonist, IMMH002, exerted a potent therapeutic effect in mice with bleomycin-induced fibrosis by protecting the integrity of the endothelial barrier. These results suggest that S1PR1 might be a promising drug target for IPF therapy."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • Transplantation • S1PR1

Fingolimod does not prevent syndecan-4 shedding from the endothelial glycocalyx in a cultured human umbilical vein endothelial cell model of vascular injury. (PubMed, Intensive Care Med Exp) - "FTY720 did not prevent syndecan-4 shedding from the EG in the HUVEC model of endothelial injury, suggesting that activation of S1PR does not prevent EG damage. FFP prevented syndecan-4 shedding from the EG via a mechanism that was independent of S1PR and upregulation of SDC-4 production. Further studies to examine whether FTY720 or another S1PR agonist might have EG-protective effects under different conditions are warranted, as are investigations seeking the mechanism of EG protection conferred by FFP in this experimental model."

Journal • Infectious Disease • Septic Shock • SDC4 • THBD • TNFA

Peptidoglycan Recognition Proteins Mediate Protection Against B. Pertussis (ASM Microbe 2022) - "Additionally, we have found that direct manipulation of TREM-1, recapitulates the anti-inflammatory ability of S1PR agonists, but with reduced off-target effects. Therefore, we believe that pharmacological targeting of this axis may be an attractive alternative to S1PR agonism and suggest that PGLYRP responses may serve as an inflammatory rheostat during infection."

Cough • Immunology • Infectious Disease • Inflammation • Pertussis • Pneumonia • Respiratory Diseases

Blocking the Migration of Circulatory T cells Mitigates the Accumulation of Allergen-induced Tissue-Resident Memory T cells (IMMUNOLOGY 2022) - "To determine the role of circulatory T cells, mice were given FTY720, a S1PR agonist. Overall, this suggests that targeting circulatory T cells during allergen insults might be employed to inhibit the accumulation of lung Trm in individuals with recent-onset asthma and may promote long-lasting airway tolerance. However, in individuals that have had asthma for some time and developed a stable population of lung Trm, targeting circulatory T cells may be ineffective in reducing the pathogenic T cell pool that maintains disease"

Asthma • CNS Disorders • Gastroenterology • Gastrointestinal Disorder • Immunology • Multiple Sclerosis • Pulmonary Disease • Respiratory Diseases • CD44 • CD69

Drug treatment strategies for eosinophilic esophagitis in adults. (PubMed, Expert Opin Pharmacother) - "Finally, the authors briefly look at the value of monoclonal antibodies targeting IL-5RA, IL-13, IL-4 or Siglec8, and oral S1PR agonists to the treatment of EoE...Investigational therapies that target several Th2-associated diseases seem useful in EoE. Comparative effectiveness and cost-utility analyses will help to position them in a complex therapeutic scenario."

Journal • Eosinophilic Esophagitis • Gastrointestinal Disorder • Immunology • Inflammation • IL13 • IL4

Fingolimod (FTY720), a Sphinogosine-1-Phosphate Receptor Agonist, Mitigates Choroidal Endothelial Proangiogenic Properties and Choroidal Neovascularization. (PubMed, Cells) - "Using laser photocoagulation rupture of Bruch's membrane to induce choroidal neovascularization, we show that S1PR non-selective (FTY720) and S1PR1 selective (CYM5442) agonists significantly inhibit choroidal neovascularization in this model. Thus, utilizing S1PR agonists to temper choroidal neovascularization presents an additional novel use for these agonists presently in clinical use for multiple sclerosis as well as other inflammatory diseases."

Journal • Age-related Macular Degeneration • CNS Disorders • Immunology • Inflammation • Macular Degeneration • Multiple Sclerosis • Ophthalmology • Retinal Disorders • Wet Age-related Macular Degeneration

Living guideline on ulcerative colitis (PubMed, Chirurg) - "For forms with a complicated course of ulcerative colitis, immunosuppressive and immunomodulating substances, such as azothioprine as well as various biologicals, Janus kinase inhibitors (JAKi), sphingosine-1-phosphate receptor agonists (S1PR agonists) and calcineurin inhibitors are available after failure of conventional treatment. A proctocolectomy should be considered in cases of a treatment-refractive course or with detection of carcinomas and high-grade epithelial dysplasia."

Journal • Review • Gastroenterology • Gastrointestinal Disorder • Immune Modulation • Immunology • Inflammation • Inflammatory Bowel Disease • Oncology • Ulcerative Colitis

Current options and investigational drugs for the treatment of eosinophilic esophagitis. (PubMed, Expert Opin Investig Drugs) - "These include monoclonal antibodies (including mepolizumab, reslizumab, benralizumab, dectrekumab, cendakimab, and dupilumab), JAK-STAT blockers and S1PR agonists, among others...Therapies under investigation potentially can target multiple Th2-associated diseases that converge in EoE patients. Therapeutic strategies require a personalized and patient-centered approach to reduce the burden of the disease, and cost-effectiveness analysis to position their use in a complex therapeutic landscape."

Journal • Eosinophilic Esophagitis • Gastrointestinal Disorder • Immunology • Inflammation

Sphingosine-1-phosphate receptor 1 agonist SEW2871 alters membrane properties of late-firing somatostatin expressing neurons in the central lateral amygdala. (PubMed, Neuropharmacology) - "NIBR application had no effect on CeL Sst neurons, indicating the absence of tonic S1P-induced S1PR. Our findings reveal subtypes of Sst neurons within the CeL that are uniquely affected by S1PR activation, which may have implications for how S1P alters supraspinal circuits."

Journal • Immunology • Inflammation • Pain

Sphingosine-1-phosphate modulates PAR1-mediated human platelet activation in a concentration-dependent biphasic manner. (PubMed, Sci Rep) - "Human platelets were treated with protease-activated receptor 1 (PAR-1)-activating peptide in the presence or absence of S1P, S1PR agonists or antagonists, and sphingosine kinases inhibitors...Although platelets express both sphingosine kinase 1/2, enzymes which phosphorylate sphingosine to produce S1P, only dual and SphK2 inhibition reduced platelet function. These results support a role for SphK2-mediated S1P generation in concentration-dependent positive and negative priming of platelet function, through S1PR1 and S1PR4/5 receptors, respectively."

Journal • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity