SPNS2 inhibitors as renal fibrosis therapy

SPNS2 抑制剂作为肾纤维化治疗

• 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
• 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

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，其特征在于细胞外基质的进行性积累。 最终破坏器官功能的基质。进行性纤维化是慢性肾病（CKD）固有的， 这通常会导致终末期肾病。虽然患者可以通过血液透析维持， 在等待移植的过程中，他们及其护理者的生活质量显著下降。而且 国家卫生系统的成本是巨大的。一种理想的药物可以逆转纤维化， 建立原始肾功能，但即使是更温和的目标，减缓纤维化进展（从而 延迟血液透析或移植的需要）仍然超出治疗范围。因此， 需要开发实验疗法。 最近的研究表明，肾周细胞中的局部鞘氨醇1-磷酸（S1 P）信号 通过在S1 P1受体活化时募集细胞因子和趋化因子来增强炎症反应。 由此产生的炎症级联反应促进纤维化。因此，在合成和运输点阻断 S1 P受体拮抗剂或S1 P1受体拮抗剂可减轻纤维化。溶质S1 P转运蛋白Spns 2 负责周细胞（但不是肾小管上皮细胞）中S1 P的细胞外释放。的s1 p 输出抑制剂可以减少炎症和纤维化。事实上，在肾纤维化小鼠模型（单侧）中， 缺血/再灌注损伤和叶酸毒性）、Spns 2的遗传缺失或用小分子抑制 与对照动物相比，显著降低了肾纤维化。综合来看， 有证据表明Spns 2抑制剂可能是治疗上有用的抗纤维化剂。Flux治疗 报道了第一个Spns 2抑制剂，显然是唯一一个拥有这种抑制剂的团队， 使公司能够将Spns 2抑制剂推向临床。为了实现这一目标，我们将从三个方面入手， 通过严格的ADME毒性、计数器筛选和药代动力学，从三种不同的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Spns 2抑制剂在以下方面的功效： 三种不同的肾脏纤维化小鼠模型。这个项目将提供一种类似药物的化合物， Spns 2作为抗纤维化药物靶点。