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: 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
• 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

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）在全球影响超过3亿个人。 β细胞功能障碍和 死亡是1型和2型糖尿病的发病机理中的关键要素。内塑性网（ER） 压力在这种β细胞下降中起重要作用。因此，靶向ER应力介导的β细胞的药物 功能障碍和死亡可以为糖尿病提供新的治疗途径。但是，目前没有 批准直接改善β细胞存活的药物。我们利用了高吞吐量筛选 （HTS）成功识别保护β细胞免受ER应激诱导死亡的小分子的方法。在 这笔赠款，我们将专注于潜在的热门歌曲之一，一种天然产品Khellin，用于铅优化和临床前 研究。我们的研究表明，在基于细胞的测定中，Khellin保护β细胞免受ER应激和 葡萄毒性诱导的功能障碍和死亡通过调节参与ER应激的基因的表达 反应，（b）khellin延迟或防止糖尿病前动物中高血糖的发作并降低血液 糖尿病动物中的葡萄糖通过保护β细胞的功能和存活，以及（c）β细胞保护作用 Khellin的抑制作用是抑制硫氧还蛋白相互作用蛋白（TXNIP）的表达（一种适配器） 将ER应激，氧化应激和炎症与细胞死亡联系起来的蛋白质。尽管具有体内效率，但 Khellin在水中固体差，口服生物利用度较差，仅在高微摩尔处活跃 浓度。因此，铅优化是必要的，以识别效力更好 和制药财产。在此提案中，我们的目标是确定这样的类似物，使血糖降低 糖尿病动物（表型靶）通过保护β细胞功能和生存（细胞靶）通过 调节参与ER应力反应（途径目标）的TXNIP表达的调节，并有所改善 物理化学和药代动力学特性，这是在有机细胞上整合药物靶标的努力 和信号通路级别，每个RFA中指定。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 钥匙ER应力标记的表达，特别是TXNIP； 2）他们的药物特性 通过药物代谢和药代动力学（DMPK）研究证明； 3）他们改善的能力 动物糖尿病模型中的高血糖和β细胞保护。为了开发这些一流的化合物，我们 将使用一种将迭代且平行的医学化学与体外和体内效率集成的方法 和DMPK研究以及计算PK和药效学（PD）建模，以确保最多 有效利用时间。