DYRK Inhibitors for Human Beta Cell Expansion

这是R-01 DK 105015的竞争续订，从16年1月3日到20年2月29日，R-01运行了四年。 该项目的重点是为1型和2型患者开发诱导人类β细胞再生的药物 糖尿病(T1D和T2D)，这两种疾病最终都是由于正常功能的β细胞数量不足造成的。 抑制激酶DYRK1a的小分子药物，如骆驼蓬碱和其他药物，具有非常高的重复性。 诱导成人β细胞复制，但复制速度较低(~2%/天)。最近，我们展示了添加 任何小分子DYRK1a对转化生长因子-β超家族抑制物(转化生长因子βI‘s)或对GLP1受体的抑制作用 激动剂(GLP1RA)，如GLP1或exendin-4，显著促进β细胞的增殖，平均促进率为5%。 8%/天，这转化为体内人类β细胞的实际数量和质量显著增加，当 移植到NOD-SCID-伽马(NSG)小鼠体内。因此，在这笔赠款期间，通过 我们自己和其他人，人类T1D和T2D的β细胞再生领域已经从不可能过渡到 显然是有可能的。 在这项拟议的更新中，我们试图了解为什么一些DYRK1A抑制剂-而不是其他-能够 促进人类β细胞分化和功能，同时也促进贝塔细胞的增殖。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(S)解释了这一令人惊讶和非常积极的影响。我们还将探索其疗效。 DYRK1A抑制剂与GLP1RA在T1D动物模型中的联合应用 和T2D，加强临床前相关性。最后，使用复杂的药物化学方法，我们 已经识别、合成并申请了专利，这是一种全新的、极其强大的人类β细胞再生能力 DYRK1A抑制剂。我们现在需要优化，使用计算预测和先进的药用化学品 合成，可切割的连接体，旨在连接我们的下一代强大和选择性的人类β细胞DYRK1A 潜在的β细胞靶向分子的抑制剂。因此，本申请的具体目标是： 1.破译精选DYRK1A抑制剂有益的促分化作用的机制。 2.确定DYRK1A抑制在1型和2型糖尿病模型中的体内疗效。 3.开发新型DYRK1A抑制剂的接头，用于靶向输送到Beta细胞。 这些目标既是可实现的，也是对NIDDK目标的直接回应。它们提供了一种 为T1D和T2D产生一种新的和迫切需要的治疗方法奠定了现实基础。

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.