SPNS2 inhibitors as renal fibrosis therapy

SPNS2 抑制剂作为肾纤维化治疗

基本信息

批准号：
10759681
负责人：
Webster L Santos
金额：
$ 30.14万
依托单位：
S1P THERAPEUTICS INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-08 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10759681
关键词：
Adverse event Agonist Autoimmune Diseases Biological Availability Blood Bradycardia Cardiac Caregivers Cells Chronic Kidney Failure Cicatrix Clinic Collagen Control Animal Creatinine Dialysis procedure Dose Drug Kinetics Drug Targeting End stage renal failure Endothelium Epithelial Cells Erythrocytes Extracellular Matrix Fibrosis Folic Acid Frequencies Generations Genetic Glomerular Filtration Rate Goals Health system Hemodialysis Immune Immunosuppression Infiltration Inflammation Inflammatory Inflammatory Response Inorganic Phosphate Transporter Investigational Therapies Ischemia Kidney Kidney Failure Lead Lyase Lymph Lymphocyte Lymphopenia Mediating Medicine Multiple Sclerosis Mus Oral Organ Pathway interactions Patients Pericytes Pharmaceutical Preparations Plasma Positioning Attribute Process Property Psoriasis Quality of life Renal function Reperfusion Injury Reporting Research Signal Transduction Sphingosine-1-Phosphate Receptor Testing Therapeutic Toxic effect Transplantation Tubular formation Ulcerative Colitis Ureteral obstruction Validation Work antagonist antifibrotic treatment chemokine comparison control cost counterscreen cytokine drug-like compound edg-1 Protein efficacy evaluation efficacy study efficacy validation extracellular genetic inhibitor genetic manipulation inhibitor kidney fibrosis knockout gene lymph nodes meter mouse model novel therapeutics pharmacodynamic biomarker programs recruit scaffold screening side effect small molecule small molecule inhibitor solute sphingosine 1-phosphate sphingosine-1-phosphate phosphatase therapeutic target trafficking wound healing

项目摘要

Fibrosis is an aberrant wound healing process characterized by progressive accumulation of extracellular matrix that ultimately destroys organ function. Progressive fibrosis is inherent to chronic kidney disease (CKD), which often leads to end-stage renal disease. Although patients can be maintained by hemodialysis while awaiting transplantation, their’s and their care-giver’s quality of life are significantly degraded. Furthermore, the costs incurred by the Nation’s health system are enormous. An ideal medicine would reverse fibrosis and re- establish pristine kidney function, but even the more modest goal of slowing fibrotic progression (and thereby delaying the need for hemodialysis or transplant) remains beyond therapeutic reach. Thus, new strategies for developing experimental therapies are needed. Recent studies indicated that local sphingosine 1-phosphate (S1P) signaling in kidney pericytes enhances the inflammatory response by recruiting cytokines and chemokines on activation of S1P1 receptor. The resulting inflammatory cascade promotes fibrosis. Thus, interdicting at the point of synthesis and transport of S1P or antagonism of S1P1 receptor can ameliorate the resultant fibrosis. The solute S1P transporter Spns2 is responsible for the extracellular release of S1P in pericytes (but not kidney tubular epithelial cells). The S1P export inhibitors can reduce inflammation and fibrosis. Indeed, in mouse models of kidney fibrosis (unilateral ischemia/reperfusion injury and folic acid toxicity), genetic deletion of Spns2 or inhibition with small molecules significantly reduced renal fibrosis as compared to control animals. Taken together, the strong preliminary evidence suggests that Spns2 inhibitors could be therapeutically useful anti-fibrotic agents. Flux Therapeutics has the first-in class Spns2 inhibitors reported and is apparently the only team with such inhibitors, which uniquely positions the company to move Spns2 inhibitors towards the clinic. To achieve this goal, we will winnow the three best compounds from three different scaffolds through rigorous ADME-tox, counter screen, and pharmacokinetic studies to identify a lead compound in Aim 1. In Aim 2, the lead Spns2 inhibitor will be validated for efficacy in three different mouse models of kidney fibrosis. This program will afford a drug-like compound that validates Spns2 as an anti-fibrotic drug target.

纤维化是一种异常的伤口愈合过程，其特征是细胞外物质的逐渐积累最终破坏器官功能的基质进行性纤维化是慢性肾病（CKD）所固有的，尽管患者可以通过血液透析维持生命，但往往会导致终末期肾病。在等待移植期间，他们及其护理人员的生活质量显着下降。国家卫生系统所花费的费用是巨大的。理想的药物可以逆转纤维化并重新治疗。建立原始的肾功能，但即使是减缓纤维化进展的更温和的目标（从而延迟血液透析或移植的需要仍然超出治疗范围，因此，新的策略仍然无法实现。需要开发实验疗法。最近的研究表明，肾脏周细胞中的局部 1-磷酸鞘氨醇 (S1P) 信号传导通过招募细胞因子和趋化因子激活 S1P1 受体来增强炎症反应。由此产生的炎症级联反应促进纤维化，从而在合成和运输点被阻断。 S1P 的作用或 S1P1 受体的拮抗作用可以改善由此产生的纤维化溶质 S1P 转运蛋白 Spns2。负责周细胞（但不包括肾小管上皮细胞）中 S1P 的细胞外释放。事实上，在肾纤维化小鼠模型中，输出抑制剂可以减少炎症和纤维化（单侧）。缺血/再灌注损伤和叶酸毒性）、Spns2 基因缺失或小分子抑制与对照动物相比，肾纤维化显着减少，初步结果强烈。有证据表明 Spns2 抑制剂可能是治疗上有用的抗纤维化药物。报道了一流的 Spns2 抑制剂，并且显然是唯一拥有此类抑制剂的团队，这具有独特性使公司能够将 Spns2 抑制剂推向临床。为了实现这一目标，我们将筛选这三种抑制剂。通过严格的 ADME-tox、反筛选和药代动力学，从三种不同支架中获得最佳化合物研究以确定目标 1 中的先导化合物。在目标 2 中，将验证先导 Spns2 抑制剂的功效该计划将提供一种可验证的药物样化合物。 Spns2 作为抗纤维化药物靶点。