Novel Selective Type II kinase Inhibitors to treat Diabetes

项目概述：1型和2型糖尿病都是由于胰腺细胞质量和功能减少所致。 因此，NIH/NIDDK的一个主要目标是开发能够导致替代和/或 人细胞的再生。这已被证明是困难的，因为成年人类细胞对 参与细胞周期进程。本项目是为了响应PAR16-121的要求，对早期水平进行扩展 新靶点、新化学支架的阶段药理学验证不是显著的重点 在生物技术和制药业的任务范围内为治疗疾病所作的努力 NIDDK。该提案的目标与这些目标和感兴趣的具体领域很好地结合在一起，包括 药物和计算化学、结构生物学和新靶点的药理学验证 糖尿病。具体地说，我们最近在2015年的《自然医学》杂志上报道了一种I型DYRK1A型激酶 抑制剂以接近治疗所需的速度激活大鼠和人类β细胞复制 人类β-细胞复制。这项工作已经发表，并得到了其他实验室的确认。 我们设想有三个部分来利用这些结果：a，DYRK1A抑制剂的优化 β细胞增殖，因为在临床开发中尚未发现此类化合物；B，组织 我们的实验室目前正在进行针对胰腺β细胞的特异性靶向，由NIDDK Grant(R01)资助 DK015015-01-A1)；C，了解免疫系统对新复制的β细胞的影响，该细胞可以 仅在成功完成组件A和B之后才能解决。 目前已知的DYRK1A抑制剂靶向于I型ATP结合的激酶口袋，并具有显著的 对进一步药物开发的责任。我们的前提是，为β的特定用途而开发的新线索- 细胞增殖将进一步证实NIDDK感兴趣的这一目标。我们的激活剂策略 优化结合强大的表型分析将导致改进的抑制剂。为此，我们有 发现了靶向失活的激酶(DFG-out类型II激酶抑制剂)的新的类药物先导。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。在此应用程序中，我们经验丰富的β-CELL团队 生物学家、计算化学家和药物化学家将追求三个特定的翻译目标： 具体目标1.开发两种新的、结构不同的II型DYRK1A型激酶/脱靶抑制剂 基于结构的药物设计用于β细胞增殖的选择性和口服生物利用度。 具体目的2.评价这些新化合物对DYRK1a、β-细胞增殖的抑制作用 使用生物化学和基于细胞的分析，优化的激酶和脱靶选择性图谱。 特定目的3.用动物评价优化的DYRK1A抑制剂对体内ADME PK的疗效 β细胞量减少模型、糖尿病动物模型及其在正常啮齿动物中的安全性。

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.