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.
项目摘要/摘要
目前有超过1亿美国人患有糖尿病或糖尿病前期,这种情况可能导致2型
糖尿病(T2D)在五年内发生,这极大地增加了心血管不良事件。T2D的特征是
由于靶组织(脂肪、骨骼肌、肝脏)对胰岛素敏感性的丧失,最终导致胰岛素受损
胰腺b细胞的分泌物。我们和其他人最近发现了一种新的离子通道信号复合体,
正向调节胰岛素介导的SWELL1/LRRC8a(富含亮氨酸重复序列的8a蛋白)
脂肪、骨骼肌和内皮的细胞内信号,胰腺β细胞的胰岛素分泌,
和全身性葡萄糖动态平衡。我们已经鉴定出一种小分子调节剂DCPIB(更名为SN-
401),作为结合SWELL1-LRRC8复合体的工具化合物,并作为分子伴侣作用于
增强SWELL1的表达和质膜转运。在体内,SN-401可使糖耐量正常化
通过增加T2D小鼠模型对胰岛素的敏感性和分泌量。SN-401增加葡萄糖在体内的摄取
脂肪组织和心肌,抑制肝脏葡萄糖的产生,保护肝脏免受
脂肪变性和肝细胞损伤。将CRYO-EM与分子对接模拟相结合,以及
我们已经验证了结构-活性关系(SAR),以生成新的SN-401同系物
T2D模型(SN-40X)的体内抗高血糖活性。我们提出小分子SWELL1
调节剂可能代表一种治疗T2D和相关疾病的一流治疗方法
通过恢复跨多个器官系统的SWELL1信号
T2D功能障碍。我们的总体目标是开发一系列领先的SN-401同类产品(SN-40X),从
选择一种先导化合物和一种后备化合物用于人体,并提交
2023年第一季度向FDA提交研究用新药(IND)申请。
目的1:在合成孔径雷达引导下对SN-40X进行体外优化和表征以提纯临床前铅
结构。
目的2:进行体内剂量范围发现毒性研究,临床前SN-40X剂量反应和
SGLT2i、埃帕利福秦和GLP1a、利拉鲁肽的正面疗效研究
目标3:在所有支持IND的cGMP条件下制造铅SN-40X化合物
以及24个月的稳定性研究和一些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)
专利数量(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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