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:
- 金额:$ 30.14万
- 依托单位:
- 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:
- 关键词:Adverse eventAgonistAutoimmune DiseasesBiological AvailabilityBloodBradycardiaCardiacCaregiversCellsChronic Kidney FailureCicatrixClinicCollagenControl AnimalCreatinineDialysis procedureDoseDrug KineticsDrug TargetingEnd stage renal failureEndotheliumEpithelial CellsErythrocytesExtracellular MatrixFibrosisFolic AcidFrequenciesGenerationsGeneticGlomerular Filtration RateGoalsHealth systemHemodialysisImmuneImmunosuppressionInfiltrationInflammationInflammatoryInflammatory ResponseInorganic Phosphate TransporterInvestigational TherapiesIschemiaKidneyKidney FailureLeadLyaseLymphLymphocyteLymphopeniaMediatingMedicineMultiple SclerosisMusOralOrganPathway interactionsPatientsPericytesPharmaceutical PreparationsPlasmaPositioning AttributeProcessPropertyPsoriasisQuality of lifeRenal functionReperfusion InjuryReportingResearchSignal TransductionSphingosine-1-Phosphate ReceptorTestingTherapeuticToxic effectTransplantationTubular formationUlcerative ColitisUreteral obstructionValidationWorkantagonistantifibrotic treatmentchemokinecomparison controlcostcounterscreencytokinedrug-like compoundedg-1 Proteinefficacy evaluationefficacy studyefficacy validationextracellulargenetic inhibitorgenetic manipulationinhibitorkidney fibrosisknockout genelymph nodesmetermouse modelnovel therapeuticspharmacodynamic biomarkerprogramsrecruitscaffoldscreeningside effectsmall moleculesmall molecule inhibitorsolutesphingosine 1-phosphatesphingosine-1-phosphate phosphatasetherapeutic targettraffickingwound 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。
项目成果
期刊论文数量(0)
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Webster L Santos其他文献
Webster L Santos的其他文献
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{{ truncateString('Webster L Santos', 18)}}的其他基金
Peptide Morphing: Rational Design of Separase Inhibitors
肽变形:分离酶抑制剂的合理设计
- 批准号:
6585224 - 财政年份:2003
- 资助金额:
$ 30.14万 - 项目类别:
Peptide Morphing: Rational Design of Separase Inhibitors
肽变形:分离酶抑制剂的合理设计
- 批准号:
6747260 - 财政年份:2003
- 资助金额:
$ 30.14万 - 项目类别:
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