Therapeutic Mitochondrial Uncouplers
治疗性线粒体解偶联剂
基本信息
- 批准号:10608112
- 负责人:
- 金额:$ 54.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-05-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:2,4-DinitrophenolAccelerationAddressAffectAnimal ModelBenchmarkingBiological AssayBiological AvailabilityBiopsyBypassCaymansCell membraneCharacteristicsChemicalsCirrhosisClinicClinicalClinical TrialsDataDietDrug KineticsEnsureEnvironmentEtiologyFDA approvedFatty LiverFatty acid glycerol estersFibrosisFunctional disorderGoalsHepaticHigh Fat DietHumanHyperthermiaImageIn VitroInflammationInner mitochondrial membraneLaboratoriesLiverLiver FailureLiver diseasesMediatingMitochondriaMitochondrial MatrixModelingMusNatureOralOxidative StressPathologyPathway interactionsPatientsPersonsPharmaceutical ChemistryPharmaceutical PreparationsPhase III Clinical TrialsPhysiologicalPopulationPrimary carcinoma of the liver cellsProcessProductionPropertyProteinsProtonsReactive Oxygen SpeciesResearchResearch PersonnelRodent ModelSafetySourceSpecificityStreptozocinStructure-Activity RelationshipTestingTherapeuticTherapeutic EffectTissuesToxic effectclinically relevantdesigndrug-like compoundefficacious treatmentefficacy validationfatty liver diseasehepatocyte injuryimprovedin vivoin vivo evaluationinnovationislet amyloid polypeptidemesoxalonitrilemetabolic ratemouse modelnon-alcoholic fatty liver diseasenonalcoholic steatohepatitisnovelnovel therapeuticsoxidationphase III trialphenylhydrazonepreservationpreventprogramsprotein transportresponsescaffoldscreeningside effectsmall moleculesuccesstool
项目摘要
PROJECT SUMMARY
The goal of this project is to develop small molecule mitochondrial uncouplers for the treatment of non-
alcoholic steatohepatitis (NASH), an advanced form of non-alcoholic fatty liver disease (NAFLD). Approximately
26 million people (~6-8% of US population) are affected by NASH, and more than 30% of patients with NASH-
related cirrhosis will die from liver failure or hepatocellular cancer. There are currently no FDA-approved drugs
to treat NASH and the top drugs in clinical trials suffer from ineffectiveness or have unwanted side effects. NASH
is characterized by fat accumulation in the liver, inflammation, and tissue remodeling. Mitochondrial uncouplers
have strong potential as NASH therapeutics by the nature of their mode of action targeting fat accumulation and
oxidative stress. Mitochondrial uncouplers transport protons from the mitochondrial intermembrane space into
the matrix bypassing ATP synthase. This process increases fat oxidation and decreases mitochondrial reactive
oxygen species production; thereby, directly targeting two pathways that underlie NASH pathophysiology that
drive inflammation and the fibrogenic response. Our laboratories have recently discovered mitochondria-
selective, safe, and orally bioavailable mitochondrial uncouplers that have wide therapeutic window. Proof-of-
principle studies in an accelerated mouse model of NASH (STAM model) achieved the FDA benchmark for
approval of a NASH therapeutic by decreasing the NAFLD Activity Score (NAS) by 2 points, with at least one
point coming from two different NAS criteria, and with no worsening of fibrosis. These strong preliminary data
support a medicinal chemistry program to improve the drug-like properties of the molecules (Aim 1) and validate
molecules in a more physiologically and clinically relevant mouse model of NASH involving Amylin diet (Aim 2).
The major innovation of our program is the discovery of novel chemical scaffolds that have different levels of
mitochondrial uncoupling capacity that are safe and self-limiting. As there are currently no drugs with a
mitochondrial uncoupling as the primary mode of action in the clinic, our program could be the first to deliver
mitochondrial uncouplers for the treatment of NASH. Indeed, this project addresses a critical need and will make
significant contribution to data supporting the validity of modulating mitochondrial uncoupling for safe and
efficacious treatment of NASH.
项目摘要
该项目的目标是开发小分子线粒体解偶联剂,用于治疗非-
酒精性脂肪性肝炎(NASH),非酒精性脂肪性肝病(NAFLD)的晚期形式。约
2600万人(约占美国人口的6-8%)受NASH影响,超过30%的NASH患者-
相关的肝硬化将死于肝衰竭或肝细胞癌。目前还没有FDA批准的药物
临床试验中的顶级药物无效或具有不希望的副作用。纳什
其特征在于肝脏中的脂肪积累、炎症和组织重塑。线粒体解偶联剂
由于其靶向脂肪积累的作用模式的性质,具有作为NASH治疗剂的强大潜力,
氧化应激线粒体解偶联剂将质子从线粒体膜间隙转运到线粒体膜上。
基质绕过ATP合成酶。这一过程增加了脂肪氧化,降低了线粒体反应性。
氧物质产生;从而,直接靶向作为NASH病理生理学基础的两个途径,
引发炎症和纤维化反应。我们的实验室最近发现了线粒体-
选择性的、安全的和口服生物可利用的线粒体解偶联剂,其具有宽的治疗窗。证明
NASH加速小鼠模型(STAM模型)的原理研究达到了FDA的基准,
通过将NAFLD活动性评分(NAS)降低2分来批准NASH治疗剂,其中至少一个
根据两种不同的NAS标准,并且没有纤维化恶化。这些强有力的初步数据
支持药物化学计划,以改善分子的药物样特性(目标1),并验证
在涉及胰淀素饮食的NASH的生理学和临床上更相关的小鼠模型中,研究了这些分子(目的2)。
我们计划的主要创新是发现了具有不同水平的化学支架,
线粒体解偶联能力是安全的和自限性的。由于目前没有药物
线粒体解偶联作为临床上的主要作用模式,我们的计划可能是第一个提供
用于治疗NASH的线粒体解偶联剂。事实上,该项目解决了一个关键的需求,
对支持调节线粒体解偶联以实现安全和有效性的数据的显著贡献
NASH的有效治疗。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Beneficial effects of simultaneously targeting calorie intake and calorie efficiency in diet-induced obese mice.
同时针对饮食诱导的肥胖小鼠的卡路里摄入量和卡路里效率的有益效果。
- DOI:10.1042/cs20231016
- 发表时间:2024
- 期刊:
- 影响因子:0
- 作者:Chen,Sing-Young;Telfser,AidenJ;Olzomer,EllenM;Vancuylenberg,CalumS;Zhou,Mingyan;Beretta,Martina;Li,Catherine;Alexopoulos,StephanieJ;Turner,Nigel;Byrne,FrancesL;Santos,WebsterL;Hoehn,KyleL
- 通讯作者:Hoehn,KyleL
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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
SPNS2 inhibitors as renal fibrosis therapy
SPNS2 抑制剂作为肾纤维化治疗
- 批准号:
10759681 - 财政年份:2023
- 资助金额:
$ 54.24万 - 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:
6585224 - 财政年份:2003
- 资助金额:
$ 54.24万 - 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:
$ 54.24万 - 项目类别:
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