Discovery and Development of Compounds to Enhance b-cell Number and Function

增强 b 细胞数量和功能的化合物的发现和开发

• 批准号: 7213132
• 负责人: Cathy A Swindlehurst
• 金额: $ 51.67万
• 依托单位: NOVOMEDIX, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7213132
• 关键词: Adult; Affect; Agreement; Amputation; Animal Model; Animals; Beta Cell; Biological; Biological Assay; Biological Models; Blindness; Bromodeoxyuridine; Cell Count; Cell Differentiation process; Cell Line; Cell Proliferation; Cell Transplantation; Cell Transplants; Cell model; Cell physiology; Cells; Cellular biology; Chemistry; Clinical; Collaborations; Data; Development; Diabetes Mellitus; Diabetic Retinopathy; Diversity Library; Drug usage; Endocrine; Equilibrium; Face; Goals; Growth; Heart Diseases; Hereditary Disease; High Blood Pressure; Human; In Vitro; Institutes; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans Transplantation; Kidney Diseases; Laboratories; Lead; Libraries; Modeling; Natural regeneration; Numbers; Pancreas; Pathway interactions; Patients; Persistent Hyperinsulinemia Hypoglycemia of Infancy; Pharmaceutical Preparations; Phase; Polymerase Chain Reaction; Preparation; Property; Purpose; Residual state; Role; Route; Running; Safety; Screening Result; Screening procedure; Series; Stem cells; Stroke; Structure; Structure-Activity Relationship; Testing; Therapeutic; Time; Toxic effect; Transplantation; United States; analog; base; blood glucose regulation; computational chemistry; cost effective; design; drug testing; embryonic stem cell; experience; high throughput screening; in vivo; interest; islet; nervous system disorder; pre-clinical; progenitor; programs; promoter; scale up; size; small molecule; success

DESCRIPTION (provided by applicant): The goal of this program is to develop and ultimately commercialize small molecule drugs that induce (-cell replication and/or differentiation for the treatment and potential cure of type 1 diabetes (T1D). Molecules that induce (-cell regeneration will be identified using high-throughput, high-content screens of small molecule compounds that act on the two major pathways by which (-cell regeneration occurs: replication of preexisting (-cells and neogenesis from endocrine progenitors within the pancreas. The first screen will identify compounds that upregulate insulin promoter activity. These compounds may be useful for inducing (-cell differentiation from precursors, either in vitro (e.g., from ES cells) to increase the supply of (-cells for transplantation or in vivo from adult progenitors. The second screen will identify compounds that repress p57Kip2 activity. These compounds may be useful for inducing (-cell replication either in vitro to increase the supply of islets for transplantation or possibly in vivo for inducing replication of the patients remaining (-cells. The insulin and p57Kip2 assays will be used to screen a 50,000 compound diversity library designed with bias towards "drug-like" properties and customized sub-libraries. Hits from initial screens will be confirmed in a panel of functionally relevant assays. Compounds that pass primary and confirmatory will be selected from both the insulin and p57kip2 assays. The goal is to identify appropriate core structures for the development of 1-3 lead series of compounds to develop Structure-Activity-Relationships (SAR) based on assay results. We anticipate synthesizing at least 25 compounds per series to explore SAR. From these compounds, 3-10 lead candidates will be selected for Phase II PK/ADMET and pre-clinical animal studies. The specific aims for this project are: 1) select and acquire a 50,000 compound screening library and design smaller focused libraries based on initial screening results, 2) identify, confirm, and characterize small molecule compounds that up-regulate insulin expression ((-cell differentiation) in a high throughput screen using a human (-cell model, 3) develop a high throughput screen for p57Kip2 expression ((-cell replication) in a human (-cell model, 4) identify, confirm, and characterize small molecule compounds that down-regulate p57Kip2 expression in a human (-cell model, and 5) develop SAR of lead molecules (1-3 lead series) and select 3-10 candidates for optimization in Phase II. The only approach that has been shown to establish and maintain normoglycemia in patients with T1D is replacement of the non-functioning (-cells via pancreas, islet, or (-cell transplant; but these are severely limited due to the shortage of donor pancreases. This proposal is focused on developing compounds that in the short term would dramatically increase the number of insulin-producing cells available for transplant and in the longer term might allow the re-establishment of the patient's own (-cells.

描述（由申请人提供）： 该计划的目的是开发并最终使诱导1型糖尿病的治疗和潜在治疗的小分子药物（-CELL复制和/或分化）（T1D）（T1D）。诱导的分子（ - 将使用高电平，高分子筛选的小分子均可鉴定出两种型号的the the the Compy of两次（cop）的分子（ - cell recemention the of the of the occouls of the occouls of occount of两次（均为）的高度分子（ preexisting (-cells and neogenesis from endocrine progenitors within the pancreas. The first screen will identify compounds that upregulate insulin promoter activity. These compounds may be useful for inducing (-cell differentiation from precursors, either in vitro (e.g., from ES cells) to increase the supply of (-cells for transplantation or in vivo from adult progenitors. The second screen will identify compounds抑制P57KIP2活性。 胰岛素和p57KIP2测定法将用于筛选50,000个复合多样性库，设计具有“药物样”特性和定制的子图案。初始屏幕的命中将在功能相关的测定面板中确认。通过胰岛素和p57KIP2分析，将选择通过原发性和确认性的化合物。目的是确定适当的核心结构，以根据测定结果开发1-3个铅系列化合物，以开发结构活性关系（SAR）。我们预计每个系列至少合成25种化合物来探索SAR。从这些化合物中，将选择3-10名铅候选者进行II期PK/ADMET和临床前动物研究。 The specific aims for this project are: 1) select and acquire a 50,000 compound screening library and design smaller focused libraries based on initial screening results, 2) identify, confirm, and characterize small molecule compounds that up-regulate insulin expression ((-cell differentiation) in a high throughput screen using a human (-cell model, 3) develop a high throughput screen for p57Kip2 expression ((-cell replication) in a human (-cell模型，4）识别，确认和表征小分子化合物，这些化合物在人（ - 细胞模型和5）中下调p57KIP2表达的表达形成了铅分子（1-3铅序列）的SAR（1-3铅序列）和选择的3-10个候选者，以在II期中优化。 唯一证明可以在T1D患者中建立和维持正常血糖的方法是替代无功能（通过胰腺，胰岛或（ - 核心移植；但是这些供体胰腺短缺）由于供体胰腺短缺而受到严重限制。由于该提议的不足。该提议的重点是在短期内增加延伸的形式，并且在短期内会增加数量的数量，并且数量不足，数量数字不足。长期可以允许重新建立患者自己的（-Cells。