Targeting SWELL1 Signaling to Treat Obesity-Induced Type 2 Diabetes
靶向 SWELL1 信号传导治疗肥胖引起的 2 型糖尿病
基本信息
- 批准号:10490426
- 负责人:
- 金额:$ 99.09万
- 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:2021-09-17 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAdipocytesAdipose tissueAmericanBackBindingBiological MarkersBlood PressureBody CompositionCardiacCardiovascular DiseasesCardiovascular systemCell membraneChemicalsChronicClinical ResearchCollaborationsComplexContractsCryoelectron MicroscopyCyclic GMPDataDiabetes MellitusDiabetes preventionDiabetic mouseDiseaseDockingDoseDrug Delivery SystemsEndotheliumEnsureEvaluationEventFatty LiverFatty acid glycerol estersFibrosisGlucoseHeadHealthHepaticHepatocyteHigh Fat DietHumanHypoglycemic AgentsImpairmentIn VitroInsulinInsulin ResistanceInvestigational DrugsInvestigational New Drug ApplicationIon ChannelLeadLeucine-Rich RepeatLiverMediatingMetabolicMetabolic syndromeMissionModelingMolecularMolecular ChaperonesMusMyocardiumNational Institute of Diabetes and Digestive and Kidney DiseasesNon-Insulin-Dependent Diabetes MellitusObesityOralOvernutritionPatientsPharmaceutical PreparationsPharmacologic SubstancePharmacologyPhasePrediabetes syndromeProteinsRegimenResearchSeriesSignal InductionSignal TransductionSiteSkeletal MuscleSocietiesStructureStructure of beta Cell of isletStructure-Activity RelationshipTestingTherapeuticTissuesToxic effectVertebral columnWorkblood glucose regulationbody systemcardiovascular disorder riskcomparative efficacydiabetes pathogenesisefficacy studyexperimental studyfasting glucoseglucose productionglucose toleranceglucose uptakeglycemic controlheart functionhemodynamicsimpaired glucose tolerancein vivoinnovationinsulin secretioninsulin sensitivityinsulin toleranceisletlead seriesliraglutidemultiple drug usenonalcoholic steatohepatitisnovelnovel therapeuticspancreatic juicepre-clinicalpreclinical efficacyprotein expressionresponsesimulationskeletalsmall moleculetooltrafficking
项目摘要
Project Summary/Abstract
More than 100 million Americans currently have diabetes or pre-diabetes, a condition that can lead to Type 2
diabetes (T2D) within five years, and that vastly increases adverse cardiovascular events. T2D is characterized
by both a loss of insulin sensitivity of target tissues (fat, skeletal muscle, liver) and ultimately, impaired insulin
secretion from the pancreatic b-cell. We, and others, recently identified a novel ion channel signaling complex,
SWELL1/LRRC8a (Leucine-rich repeat containing protein type 8a) that positively regulates insulin-mediated
intracellular signaling in adipose, skeletal muscle, and endothelium, insulin secretion from pancreatic β-cells,
and systemic glucose homeostasis. We have identified a small molecule modulator, DCPIB (renamed SN-
401), as a tool compound that binds the SWELL1-LRRC8 complex and functions as a molecular chaperone to
augment SWELL1 expression and plasma membrane trafficking. In vivo, SN-401 normalizes glucose tolerance
by increasing insulin sensitivity and secretion T2D mouse models. SN-401 augments glucose uptake into
adipose tissue and myocardium, suppresses hepatic glucose production, and protects against hepatic
steatosis and hepatocyte damage. Combining cryo-EM with molecular docking simulations, and functional
studies we have validated a structure-activity relationship (SAR) to generate novel SN-401 congeners with in
vivo anti-hyperglycemic activity in T2D models (SN-40X). We propose that small molecule SWELL1
modulators may represent a first-in-class therapeutic approach to treat T2D and associated
cardiovascular disease by restoring SWELL1 signaling across multiple organ systems that are
dysfunctional in T2D. Our overall objective is to develop a lead series of SN-401 congeners (SN-40X) from
which to select one lead compound and one back-up to take into humans, with submission of an
Investigational New Drug (IND) application to the FDA in Q1 of 2023.
AIM 1: SAR-directed SN-40X optimization and characterization in vitro to refine preclinical lead
structures.
AIM 2: Perform in vivo dose-range finding toxicity studies, pre-clinical SN-40X dose-response and
head-to-head efficacy studies against SGLT2i, empagliflozin and GLP1a, liraglutide
AIM 3: Manufacture the lead SN-40X compound under cGMP conditions required for all IND-enabling
and 24-month stability studies and some Phase I clinical studies.
项目总结/摘要
目前有超过1亿美国人患有糖尿病或糖尿病前期,这种疾病可能导致2型糖尿病
五年内就会出现糖尿病(T2 D),这会大大增加不良心血管事件。T2 D的特点是
由于靶组织(脂肪、骨骼肌、肝脏)的胰岛素敏感性丧失,
胰腺B细胞分泌物。我们和其他人最近发现了一种新的离子通道信号复合物,
SWELL 1/LRRC 8a(富含亮氨酸重复序列的蛋白质8a型),正调节胰岛素介导的
脂肪、骨骼肌和内皮中的细胞内信号传导,胰腺β细胞的胰岛素分泌,
和全身葡萄糖稳态。我们已经鉴定了一种小分子调节剂DCPIB(重命名为SN-1)。
401),作为结合SWELL 1-LRRC 8复合物的工具化合物,并作为分子伴侣发挥作用,
增加SWELL 1表达和质膜运输。在体内,SN-401使葡萄糖耐量正常化
通过增加T2 D小鼠模型的胰岛素敏感性和分泌。SN-401增加葡萄糖摄取,
脂肪组织和心肌,抑制肝脏葡萄糖的产生,并保护肝脏免受
脂肪变性和肝细胞损伤。将冷冻EM与分子对接模拟相结合,
我们已经验证了构效关系(SAR),以产生新的SN-401同系物,
T2 D模型中的体内抗高血糖活性(SN-40 X)。我们认为小分子SWELL 1
调节剂可能代表了治疗T2 D及其相关疾病的一流治疗方法
通过恢复跨多个器官系统的SWELL 1信号传导,
2型糖尿病的功能障碍我们的总体目标是开发一系列SN-401同系物(SN-40 X),
选择一种先导化合物和一种备用化合物进入人体,
2023年第一季度向FDA提交研究性新药(IND)申请。
目的1:SAR导向的SN-40 X体外优化和表征,以优化临床前电极导线
结构.
目的2:进行体内剂量范围探索毒性研究、临床前SN-40 X剂量反应和
针对SGLT 2 i、恩格列净和GLP 1a、利拉鲁肽的头对头疗效研究
目的3:在所有IND启用所需的cGMP条件下生产SN-40 X先导化合物
以及24个月稳定性研究和一些I期临床研究。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Daniel J Lerner其他文献
Daniel J Lerner的其他文献
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{{ truncateString('Daniel J Lerner', 18)}}的其他基金
Targeting SWELL1 Signaling to Treat Obesity-Induced Type 2 Diabetes
靶向 SWELL1 信号传导治疗肥胖引起的 2 型糖尿病
- 批准号:
10384448 - 财政年份:2021
- 资助金额:
$ 99.09万 - 项目类别:
Optimizing SWELL1 modulators to treat non-alcoholic steatohepatitis
优化 SWELL1 调节剂治疗非酒精性脂肪性肝炎
- 批准号:
10461207 - 财政年份:2020
- 资助金额:
$ 99.09万 - 项目类别:
Optimizing SWELL1 modulators to treat non-alcoholic steatohepatitis
优化 SWELL1 调节剂治疗非酒精性脂肪性肝炎
- 批准号:
10081592 - 财政年份:2020
- 资助金额:
$ 99.09万 - 项目类别:
Optimizing SWELL1 modulators to treat non-alcoholic steatohepatitis
优化 SWELL1 调节剂治疗非酒精性脂肪性肝炎
- 批准号:
10397716 - 财政年份:2020
- 资助金额:
$ 99.09万 - 项目类别:
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