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：
9353780
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 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9353780
关键词：
Adaptor Signaling Protein Affect Ammi visnaga Animals Asthma B Cell Proliferation Beta Cell Binding Proteins Biological Biological Assay Biological Availability Blood Glucose Cell Death Cell Survival Cell physiology Cells Cellular Assay Cessation of life Chemicals Complex Coronary heart disease Cytoprotection Data Diabetes Mellitus Diabetic mouse Disease Drug Kinetics Drug Targeting Eating Elements Ensure Excretory function Functional disorder Gene Expression Goals Grant Half-Life Hyperglycemia In Vitro Individual Inflammation Insulin Insulin Resistance Insulin-Dependent Diabetes Mellitus Islet Cell 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 Pathologic Pathway interactions Patients Peripheral Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Pharmacotherapy Phenotype Plant Extracts Plasma Play Positioning Attribute Property Protective Agents Public Health Research Role Signal Pathway Solubility Specific qualifier value Standardization Stress Structure Structure of beta Cell of islet Structure-Activity Relationship TXNIP gene Testing Toxic effect Transplantation Treatment Efficacy Water Weight Gain Work absorption analog base biological adaptation to stress cellular targeting clinical development db/db mouse diabetic drug metabolism endoplasmic reticulum stress high throughput screening improved in vivo insight insulin secretion insulin sensitivity novel novel therapeutics pharmacodynamic model preclinical development preclinical study prevent protective effect small molecule systemic toxicity time use

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.

抽象的 2 型糖尿病 (T2D) 影响全球 3 亿多人，β 细胞功能障碍。死亡是 1 型和 2 型糖尿病发病机制的关键因素。应激在β细胞衰退中起着重要作用，因此，针对内质网应激介导的β细胞的药物。功能障碍和死亡可能为糖尿病提供新的治疗途径，但目前还没有。我们利用高通量筛选批准了直接提高β细胞存活率的药物。 (HTS) 方法成功识别了保护 β 细胞免受 ER 应激诱导死亡的小分子。这笔资助，我们将重点关注其中一个有效的热门产品，即用于先导优化和临床前的天然产品 Khellin 我们的研究表明，(a) 在基于细胞的检测中，Khellin 可以保护 β 细胞免受 ER 应激和影响。通过调节内质网应激相关基因的表达，糖毒性诱导功能障碍和死亡 (b) Khellin 延迟或预防糖尿病前期动物高血糖的发生并降低血糖通过保护 β 细胞的功能和存活来降低糖尿病动物体内的葡萄糖含量，以及 (c) β 细胞保护作用 Khellin 的作用是通过抑制硫氧还蛋白相互作用蛋白 (TXNIP) 的表达来介导的，TXNIP 是一种接头蛋白将内质网应激、氧化应激和炎症与细胞死亡联系起来的蛋白质尽管具有体内功效， Khellin 难溶于水，口服生物利用度差，仅在高微摩尔浓度下才有活性因此，有必要对先导化合物进行优化，以确定具有更好效力的 Khellin 类似物。在本提案中，我们的目标是确定能够降低血糖的类似物。糖尿病动物（表型目标）通过保护 β 细胞功能和存活（细胞目标）调节参与 ER 应激反应（途径目标）的 TXNIP 表达，改善理化和药代动力学特性，将药物靶标整合到生物、细胞、为了实现这些目标，我们计划 1) 合成 Khelin。类似物以提高其在基于细胞的测定中促进 β 细胞存活的生物效力及其对关键 ER 应激标记物的表达，特别是 TXNIP 2) 它们的药理学特性，如通过药物代谢和药代动力学 (DMPK) 研究证明；3) 其改善的能力；为了开发这些一流的化合物，我们在动物糖尿病模型中研究高血糖和 β 细胞保护。将使用一种将迭代和并行药物化学与体外和体内功效相结合的方法和 DMPK 研究以及计算 PK 和药效 (PD) 模型，以确保最有效利用时间。