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）： 该计划的目标是开发并最终商业化诱导β细胞复制和/或分化的小分子药物，用于治疗和潜在治愈1型糖尿病（T1 D）。诱导β-细胞再生的分子将使用小分子化合物的高通量、高含量筛选来鉴定，所述小分子化合物作用于发生β-细胞再生的两个主要途径：预先存在的β-细胞的复制和来自胰腺内的内分泌祖细胞的新生。第一次筛选将鉴定上调胰岛素启动子活性的化合物。这些化合物可用于在体外（例如，来自ES细胞）以增加用于移植或体内来自成体祖细胞的β-细胞的供应。第二次筛选将鉴定抑制p57 Kip 2活性的化合物。这些化合物可用于在体外诱导β-细胞复制以增加用于移植的胰岛的供应，或可能在体内诱导患者剩余β-细胞的复制。 胰岛素和p57 Kip 2测定将用于筛选50，000个化合物多样性文库，该文库设计为偏向“药物样”性质和定制的子文库。将在一组功能相关试验中确认初始筛选的命中。将从胰岛素和p57 kip 2试验中选择通过初步和确证性试验的化合物。目标是确定适当的核心结构，用于开发1-3个先导系列化合物，以根据测定结果开发结构-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种先导候选药物用于II期PK/ADMET和临床前动物研究。 该项目的具体目标是：1）选择和获得50，000个化合物筛选文库，并基于初始筛选结果设计较小的聚焦文库，2）鉴定、确认和表征上调胰岛素表达的小分子化合物（（-细胞分化）在使用人类的高通量筛选中，（-细胞模型，3）开发用于p57 Kip 2表达的高通量筛选（（-细胞复制）在人体内（-细胞模型，4）鉴定、确认和表征下调人p57 Kip 2表达的小分子化合物（-细胞模型，和5）开发先导分子（1-3个先导系列）的SAR，并选择3-10个候选物用于第II阶段的优化。 已证明在T1 D患者中建立和维持正常血糖的唯一方法是通过胰腺、胰岛或β-细胞移植替换无功能的β-细胞;但由于供体胰腺的短缺，这些方法受到严重限制。这项提议的重点是开发一种化合物，在短期内将大大增加可用于移植的胰岛素产生细胞的数量，在长期内可能允许重建患者自己的β细胞。