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.

摘要 全球有超过3亿人患有2型糖尿病(T2D)。β细胞功能障碍和 死亡是1型和2型糖尿病发病机制中的关键因素。内质网(ER) 压力在这种β细胞衰退中起着重要作用。因此，靶向内质网应激介导的β细胞的药物 功能障碍和死亡可能为糖尿病提供一种新的治疗途径。然而，目前还没有 已批准的直接提高β细胞存活率的药物。我们使用了高通量筛查 成功识别保护β细胞免受内质网应激诱导死亡的小分子的方法。在……里面 这笔拨款，我们将专注于一种强有力的热门产品，一种用于领先优化和临床前研究的天然产品Khellin 学习。我们的研究表明：(A)在基于细胞的分析中，Khellin保护β细胞免受内质网应激--和 糖毒性通过调节内质网应激相关基因的表达而导致功能障碍和死亡 反应，(B)Khellin延缓或预防糖尿病前期动物高血糖的发生并降低血液 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细胞的保护作用 Khellin的表达是通过抑制接头硫氧还蛋白相互作用蛋白(TXNIP)的表达而介导的 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。尽管它在体内有效， 凯林在水中难溶，口服生物利用度差，仅在高微摩尔时有效。 浓度。因此，有必要进行先导优化，以确定具有更好效力的Khellin类似物 和药理作用。在这项提议中，我们的目标是识别这样的类似物，在 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) 参与内质网应激反应的TXNIP表达的调节(通路靶点)，并改善 物理化学和药代动力学特性，一种将药物靶标整合到生物，细胞， 和信号通路水平，每个都在本RFA中指定。为了实现这些，我们计划1)合成柯林 在基于细胞的检测中提高其促进β细胞存活的生物学效力的类似物及其对 关键的内质网应激标志物，特别是TXNIP的表达；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；以及3)它们的改善能力 糖尿病动物模型中的高血糖和β细胞保护。为了开发这些一流的化合物，我们 将使用一种将迭代和并行药物化学与体外和体内疗效相结合的方法 和DMPK研究以及计算PK和药效学(PD)建模，以确保最 有效利用时间。