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

描述(由申请人提供)： 该计划的目标是开发小分子药物并最终将其商业化，这些药物可以诱导细胞复制和/或分化，用于治疗和潜在治愈1型糖尿病(T1D)。诱导(-细胞再生的分子将通过高通量、高含量的小分子化合物筛选来识别，这些小分子化合物作用于发生(-细胞再生的两条主要途径：复制先前存在的(-细胞和胰腺内内分泌前体细胞的新生。第一个筛选将确定上调胰岛素启动子活性的化合物。这些化合物可能有助于从前体细胞诱导(-细胞)分化，无论是在体外(例如，来自ES细胞)以增加移植的(-细胞)的供应，还是在体内从成体祖细胞诱导(-细胞分化)。第二个筛选将确定抑制p57Kip2活性的化合物。这些化合物可能有助于在体外诱导(-细胞)复制以增加供移植的胰岛供应，或者可能在体内诱导患者剩余(-细胞)的复制。 胰岛素和p57Kip2检测将用于筛选50,000个化合物多样性文库，这些文库偏向于“类药物”性质和定制的子文库。来自初始屏幕的命中将在一组功能相关的分析中得到确认。通过初选和确证的化合物将从胰岛素和p57Kip2试验中选择。目标是为开发1-3个铅系列化合物确定合适的核心结构，以根据分析结果开发结构-活性-关系(SAR)。我们预计每个系列至少合成25个化合物来探索SAR。从这些化合物中，将选出3-10个候选先导化合物用于第二阶段PK/ADMET和临床前动物研究。 该项目的具体目的是：1)选择并获得50,000个化合物筛选文库，并基于初始筛选结果设计更小的聚焦文库；2)使用人类细胞模型在高通量筛选中鉴定、确认和表征上调胰岛素表达(细胞分化)的小分子化合物；3)在人类细胞模型中开发p57Kip2表达(细胞复制)的高通量筛查；4)识别、确认和表征在人类细胞模型中下调p57Kip2表达的小分子化合物，5)开发铅分子(1-3个铅系列)的合成孔径雷达，选择3-10个候选进行二期优化。 已被证明在T1D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(细胞)移植替换无功能的(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化合物，这些化合物在短期内将显著增加可用于移植的胰岛素产生细胞的数量，从长远来看，可能允许重建患者自己的(细胞)。

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.