Novel Selective Type II kinase Inhibitors to treat Diabetes

项目概要：1型和2型糖尿病都是由于胰腺癌细胞数量和功能的减少而引起的. 因此，NIH/NIDDK的一个主要目标是开发新的药物和工具，可以导致替代和/或治疗。 再生人类胰岛细胞。这已被证明是困难的，因为成年人的胰岛细胞是难治性的。 参与细胞周期进程。本项目是为了响应PAR 16 -121延长水平的早期 阶段药理学验证的新目标，新的化学支架，不是重点的重要 在生物技术和制药工业中为治疗联合国使命范围内的疾病所作的努力 NIDDK。本提案的目标与这些目标和具体关注领域非常一致，包括 药物和计算化学，结构生物学和药理学验证的新目标， 糖尿病具体来说，我们最近在2015年的《自然医学》上报道，I型DYRK 1A激酶 抑制剂以接近治疗所需的速率激活大鼠和人β细胞复制 人β细胞复制。这项工作已发表并得到其他实验室的证实。 我们设想了三个组成部分来利用这些结果：A，DYRK 1A抑制剂的优化， β细胞增殖，因为在临床开发中没有该类已知化合物; B，组织 目前，我们的实验室正在进行胰腺β细胞的特异性靶向研究，该研究由NIDDK资助（R 01 DK 015015 -01-A1）; C，了解免疫系统对新复制的β细胞的影响，这可以 只有在成功完成A和B部分后才能解决。 目前已知的DYRK 1A抑制剂靶向激酶的I型ATP结合口袋，并且具有显著的生物学活性。 进一步开发药物的责任。我们的前提是，为β - 细胞增殖将为NIDDK提供该目标的进一步验证。我们的激酶策略 最优化与强大的表型分析相结合将导致改进的抑制剂。为此，我们 鉴定了靶向非活性激酶的新型药物样先导物（DFG-out II型激酶抑制剂）。这些结果 为药物发现工作提供基础，包括分子靶点、体外/体内β细胞生物学，以及 药物化学优化的可行起点。在此应用中，我们经验丰富的β细胞团队 生物学家，计算和药物化学家将追求三个翻译具体目标： 具体目标1。开发两种新的、结构不同的II型DYRK 1A抑制剂，具有激酶/脱靶作用 选择性和口服生物利用度的β细胞增殖使用基于结构的药物设计。 具体目标2。评估这些新型化合物对DYRK 1A、β细胞增殖和 功能，优化的激酶和脱靶选择性概况使用生化和细胞为基础的测定。 具体目标3。使用动物模型评价优化的DYRK 1A抑制剂的体内ADME PK、疗效 减少的β细胞质量模型、糖尿病动物模型及其在正常啮齿动物中的安全性特征。

Project Summary: Both Type 1 and 2 diabetes result from reductions in pancreatic -cell mass and function. Thus, a major goal of the NIH/NIDDK is to develop novel drugs and tools that can lead to replacement and/or regeneration of human -cells. This is has proven difficult, because adult human -cells are refractory to engagement in cell cycle progression. This project is in response to PAR16-121 to extend the level of early stage pharmacological validation of novel targets, novel chemical scaffolds that are not the focus of significant efforts in the biotechnology and pharmaceutical industry for treatment of diseases within the mission of the NIDDK. The goals of this proposal align well with these objectives and specific areas of interest including medicinal and computational chemistry, structural biology and pharmacological validation of novel targets for diabetes. Specifically, we have recently reported in Nature Medicine in 2015 that a type I DYRK1A kinase inhibitor activates both rat and human β-cell replication at rates that approach those required for therapeutic human β-cell replication. This work was published and confirmed by other labs. We envision three components to exploiting these results: A, Optimization of DYRK1A inhibitors for beta cell proliferation since there are NO known compounds of this class in clinical development; B, Tissue Specific Targeting to pancreatic beta cells currently underway in our labs funded by NIDDK grant (R01 DK015015-01-A1); C, Understanding the effects of the immune system on newly replicated beta cell which can only be addressed after successfully completing components A and B. Current known DYRK1A inhibitors target the type I ATP-binding pocket of kinases and have significant liabilities for further drug development. Our premise is that novel leads, developed for the specific use for β - cell proliferation will provide further validation of this target of interest to NIDDK. Our strategy of kinase optimization coupled with powerful phenotypic assays will lead to improved inhibitors. To that end, we have identified novel drug-like leads that target the inactive kinase (DFG-out type II kinase inhibitors). These results provide the basis for a drug discovery effort that includes a molecular target, in vitro/in vivo β-cell biology, and viable starting points for medicinal chemistry optimization. In this application, our experienced team of β-cell biologists, computational and medicinal chemists will pursue three translational Specific Aims: Specific Aim 1. Develop two novel, structurally distinct type II DYRK1A inhibitors with kinase/off-target selectivity and oral bioavailability for β-cell proliferation using structure-based drug design. Specific Aim 2. Evaluate these novel compounds for inhibition of DYRK1A, β-cell proliferation and function, optimized kinase and off-target selectivity profiles using biochemical and cell-based assays. Specific Aim 3. Evaluate optimized DYRK1A inhibitors for in vivo ADME PK, efficacy using animal models of reduced β-cell mass, diabetic animal models and their safety profiles in normal rodents.