DYRK Inhibitors for Human Beta Cell Expansion

这是R-01 DK 105015的竞争性更新，从2016年3月1日到2020年2月29日运行了四年。的 该项目的重点是开发药物，诱导人类β细胞再生的人1型和2型 糖尿病（T1 D和T2 D），这两种疾病最终都是由正常功能的β细胞数量不足引起的。 抑制激酶DYRK 1A的小分子药物，如去氢骆驼蓬碱和其他药物， 诱导成人β细胞复制，但速率较低（约2%/天）。最近，我们已经证明， TGF-β超家族抑制剂（TGFβI）或GLP 1受体的任何小分子DYRK 1A抑制剂 激动剂（GLP 1 RA），如GLP 1或毒蜥外泌肽-4，显著增强β细胞增殖至平均5- 8%/天，并且这转化为体内人β细胞的实际数量和质量的显著增加，当 移植到NOD-SCID-γ（NSG）小鼠中。因此，在此期间的赠款，通过工作， 我们自己和其他人，T1 D和T2 D的人类β细胞再生领域已经从不可能过渡到 显然是可能的。 在这个提议的更新中，我们试图了解为什么一些DYRK 1A抑制剂-而不是其他-能够 增强人β细胞分化和功能，同时还驱动β细胞增殖。维持β细胞 分化将是任何β细胞再生药物的基本特征。我们希望找出潜在的 信号通路解释了这种令人惊讶的和非常积极的影响。我们还将探讨 DYRK 1A抑制剂与GLP 1 RA联合用于T1 D的基本但以前未探索的动物模型 和T2 D，加强临床前相关性。最后，使用复杂的药物化学方法，我们 已经鉴定，合成和专利完全新颖和极其有效的人类β细胞再生 DYRK 1A抑制剂。我们现在需要优化，使用计算预测和先进的药物化学 合成，设计用于连接我们的下一代有效和选择性人β细胞DYRK 1A的可切割接头 潜在β细胞靶向分子的抑制剂。因此，本申请的具体目的是： 1.选择DYRK 1A抑制剂的有益促分化作用的基础机制。 2.定义DYRK 1A抑制在1型和2型糖尿病模型中的体内功效。 3.开发新型DYRK 1A抑制剂的接头，用于靶向递送至β细胞。 这些目标都是可以实现的，并且直接响应了《国家残疾人权利公约》的目标。他们提供了一个 这是为T1 D和T2 D产生新的和迫切需要的一类疗法的现实基础。

This is a competing renewal for R-01 DK 105015, which ran for four years from 3/01/16 to 2/29/20. The project focuses on developing drugs that induce human beta cells to regenerate for people with Type 1 and Type 2 diabetes (T1D and T2D), both of which ultimately result from inadequate numbers of normally functioning beta cells. Small molecule drugs that inhibit the kinase, DYRK1A, such as harmine and others, are very reproducibly able to induce adult human beta cells to replicate, but at low rates (~2%/day). More recently, we have shown that adding any small molecule DYRK1A inhibitor to either a TGF-beta superfamily inhibitor (TGFβI’s) or to a GLP1 receptor agonist (GLP1RA), such as GLP1 or exendin-4, markedly enhances beta cell proliferation to rates averaging 5- 8%/day, and that this translates to marked increases in actual numbers and mass of human beta cells in vivo, when transplanted into NOD-SCID-gamma (NSG) mice. Thus, during the period of this grant, through the work of ourselves and others, the field of human beta cell regeneration for T1D and T2D has transitioned from impossible to clearly possible. In this proposed renewal, we seek to learn why some DYRK1A inhibitors - but not others - are able to enhance human beta cell differentiation and function, while also driving beta cell proliferation. Maintaining beta cell differentiation will be an essential feature of any beta cell regenerative drug. We expect to identify the underlying signaling pathway(s) that explain this surprising and very positive effect. We also will explore the efficacy of DYRK1A inhibitors, in combination with GLP1RA’s, in essential but previously unexplored animal models of T1D and T2D, strengthening pre-clinical relevance. Finally, using sophisticated medicinal chemistry approaches, we have identified, synthesized and patented entirely novel and extremely potent human beta cell regenerative DYRK1A inhibitors. We now need to optimize, using computational predictions and advanced medicinal chemical syntheses, cleavable linkers designed to attach our next-generation potent and selective human beta cell DYRK1A inhibitors to potential beta cell-targeting molecules. Thus, the Specific Aims of this application are to: 1. Decipher Mechanisms Underlying the Beneficial Pro-Differentiation Effects of Select DYRK1A Inhibitors. 2. Define in vivo Efficacy of DYRK1A inhibition in Type 1 and Type 2 Diabetes Models. 3. Develop Linkers to Novel Classes of DYRK1A Inhibitors for Targeted Delivery to Beta Cells. These goals are both achievable and directly responsive to the goals of aims of the NIDDK. They provide a realistic basis for generating a new and urgently needed class of therapeutics for T1D and T2D.