权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Preclinical Development of Khellin Analogs for Anti-Diabetic Therapy

用于抗糖尿病治疗的 Khellin 类似物的临床前开发

基本信息

批准号：
9336063
负责人：
Weidong Wang
金额：
$ 22.2万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-20 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9336063
关键词：
Adaptor Signaling Protein Affect Animals Asthma Beta Cell Binding Proteins Biological Biological Assay Biological Availability Blood Glucose Cell Death Cell Proliferation Cell Survival Cell physiology Cells Cellular Assay Cessation of life Chemicals Clinical Complex Coronary heart disease Cytoprotection Data Development Diabetes Mellitus Diabetic mouse Disease Drug Kinetics Drug Targeting Eating Ensure Excretory function Functional disorder Gene Expression Goals Grant Half-Life Hyperglycemia In Vitro Indium Individual Inflammation Insulin Insulin Resistance Islets of Langerhans Transplantation Lead Maintenance Mediating Metabolic Metabolism Modeling Molecular Mus Natural Products Non-Insulin-Dependent Diabetes Mellitus Obesity Oral Organ Oxidative Stress Pathogenesis Pathway interactions Patients Peripheral Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacotherapy Plant Extracts Plasma Play Positioning Attribute Property Protective Agents Public Health Research Role Signal Pathway Solubility Specific qualifier value Stress Structure Structure of beta Cell of islet Structure-Activity Relationship TXNIP gene Testing Therapeutic Toxic effect Transplantation Water Weight Gain Work absorption abstracting analog base biological adaptation to stress cellular targeting db/db mouse diabetic drug metabolism endoplasmic reticulum stress high throughput screening improved in vivo insight insulin secretion insulin sensitivity islet novel novel therapeutics pharmacodynamic model pre-clinical preclinical study prevent protective effect protein expression small molecule systemic toxicity time use type I and type II diabetes

项目摘要

Abstract Type 2 Diabetes (T2D) affects more than 300 million individuals globally. Beta cell dysfunction and death are key elements in the pathogenesis of both type 1 and type 2 diabetes. Endoplasmic reticulum (ER) stress plays important role in this beta cell decline. Therefore, drugs that target ER stress-mediated β cell dysfunction and death could provide a new therapeutic avenue for diabetes. However, there are currently no approved drugs that directly improve the survival of β cells. We have utilized a high throughput screening (HTS) approach to successfully identify small molecules that protect β cell from ER stress-induced death. In this grant, we will focus on one of the potent hits, a natural product Khellin for lead optimization and preclinical studies. Our studies revealed that (a) in cell-based assays, Khellin protects β cells against ER stress- and glucotoxicity-induced dysfunction and death by modulating the expression of genes involved in ER stress responses, (b) Khellin delays or prevents the onset of hyperglycemia in prediabetic animals and lowers blood glucose in diabetic animals by protecting the function and survival of β cells, and (c) the β cell-protective effect of Khellin is mediated by suppression of the expression of thioredoxin-interacting protein (TXNIP), an adaptor protein that connects ER stress, oxidative stress, and inflammation with cell death. Despite its in vivo efficacy, Khellin is poorly soluble in water, has poor oral bioavailability, and is only active at high micromolar concentrations. Therefore, lead optimization will be necessary to identify Khellin analogs with better potency and pharmacological property. In this proposal, our goal is to identify such analogs that lower blood glucose in diabetic animals (phenotypic target) by protecting β cell function and survival (cellular target) through the modulation of expression of TXNIP involved in ER stress response (pathway target), with improved physicochemical and pharmacokinetic properties, an effort integrating drug targets at the organismal, cellular, and signaling pathway levels, each as specified in this RFA. To achieve these, we plan to 1) synthesize Khelin analogs to improve their biological potency in promoting β cell survival in cell-based assays and their effect on expression of key ER stress markers, TXNIP in particular; 2) their pharmacological properties, as demonstrated by drug metabolism and pharmacokinetic (DMPK) studies; and 3) their ability to ameliorate hyperglycemia and β cell protection in animal diabetes models. To develop these first-in-class compounds, we will use an approach that integrates iterative and parallel medicinal chemistry with in vitro and in vivo efficacy and DMPK studies as well as a computational PK and pharmacodynamic (PD) modeling to ensure the most efficient use of time.

摘要