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

• 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
• 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

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 2型糖尿病（T2 D）影响全球超过3亿人。β细胞功能障碍， 死亡是1型和2型糖尿病发病机制中的关键因素。内质网 压力在这种β细胞下降中起着重要作用。因此，靶向ER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。然而，目前没有 直接改善β细胞存活的获批药物。我们利用高通量筛选 (HTS)成功鉴定保护β细胞免受ER应激诱导死亡的小分子的方法。在 在这笔赠款中，我们将专注于其中一个有效的命中，一种天然产品Khellin用于铅优化和临床前研究。 问题研究我们的研究表明，（a）在基于细胞的测定中，Khellin保护β细胞免受ER应激， 通过调节参与ER应激的基因表达来抑制葡萄糖毒性诱导的功能障碍和死亡 （B）Khellin延迟或防止糖尿病前期动物中高血糖症的发作，并降低血液中的糖代谢。 通过保护β细胞的功能和存活，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， 连接内质网应激、氧化应激和炎症与细胞死亡的蛋白质。尽管它在体内有效， Khellin难溶于水，口服生物利用度差，并且仅在高微摩尔浓度下才有活性。 浓度的因此，先导物优化将是必要的，以确定具有更好效力的Khellin类似物 和药理学性质。在这项提案中，我们的目标是确定这样的类似物，降低血糖， 糖尿病动物（表型靶点）通过保护β细胞功能和存活（细胞靶点）， 调节参与ER应激反应的TXNIP表达（途径靶点）， 物理化学和药代动力学特性，努力整合药物靶点在有机体，细胞， 和信号传导途径水平，均在本RFA中规定。为了实现这些，我们计划1）合成Khelin 在基于细胞的测定中提高它们在促进β细胞存活中的生物学效力的类似物以及它们对 关键ER应激标志物，特别是TXNIP的表达; 2）它们的药理学性质， 通过药物代谢和药代动力学（DMPK）研究证实;和3）它们改善 高血糖和β细胞保护的作用。为了开发这些一流的化合物，我们 将使用一种方法，将迭代和平行的药物化学与体外和体内疗效相结合 和DMPK研究以及计算PK和药效学（PD）建模，以确保最大限度地 有效利用时间。