Dyrk Inhibitors for Human Beta Cell Expansion

 描述（由申请人提供）：1型和2型糖尿病均由胰腺β细胞质量和功能减少引起。因此，NIH/NIDDK的一个主要目标是开发新的药物和工具，可以导致人类β细胞的替代和/或再生。这已被证明是困难的，因为成年人β细胞难以参与细胞周期进程。最近，我们设计并进行了两个小分子文库的独特高通量筛选（HTS），一个2000化合物FDA文库和第二个100，000化合物文库，并鉴定了一种新型有效的小分子，去氢骆驼蓬碱，它能够以接近治疗性人类β细胞复制所需的速率激活小鼠，大鼠和人类β细胞复制。我们还鉴定了与去氢骆驼蓬碱共享结构和功能特征的其他化合物，并将其称为“骆驼蓬碱”。正在进行的结构-活性研究表明，这些化合物采用的共同途径是钙调神经磷酸酶-NFaT-DYRK 1A途径，但其他途径和细胞内靶点仍然是可能的。至于β细胞生物学的广泛领域，将harmalogs靶向β细胞是具有挑战性的。因此，在本申请中，我们组建了一个由经验丰富的β细胞生物学家和药物化学家组成的团队，以实现三个特定目标：1.充分确定“Harmalogs”对人β细胞增殖的作用机制。2.记录“有害类似物”对人β细胞扩增和功能的体内作用。3.合成具有化学接头的修饰的Harmalogs，其允许保留生物活性并与β细胞靶向配体缀合。我们相信这些研究是非常重要的，因为它们记录了成年人β细胞可以使用小分子方法以治疗相关的速率诱导增殖;它们将定义药物类化合物的分子作用机制;并且，因为它们探索了将这些有效的再生化合物靶向人类β细胞的新方法。

 DESCRIPTION (provided by applicant): Both Types 1 and 2 diabetes result from reductions in pancreatic beta 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 beta cells. This is has proven difficult, because adult human beta cells are refractory to engagement in cell cycle progression. Recently, we designed and performed a unique high-throughput screen (HTS) of two small molecule libraries, a 2000 compound FDA library and a second 100,000 compound library, and have identified a novel and effective small molecule, harmine, that is able to activate mouse, rat and human beta cell replication at rates that approach those required for therapeutic human beta cell replication. We have also identified additional compounds that share structural and functional features with harmine, and refer to them as "harmalogs". Ongoing structure-activity studies suggest that the common pathway employed by these compounds is a calcineurin-NFaT-DYRK1A pathway, but additional pathways and intracellular targets remain possible. As for the broad field of beta cell biology in general, targeting harmalogs to beta cells is challenging. Accordingly, in this application, we assemble a team of experienced beta cell biologists and medicinal chemists to pursue three Specific Aims: 1. To Fully Define the Mechanism of Action of the "Harmalogs" on Human Beta Cell Proliferation. 2. To Document In Vivo Effects of the "Harmalogs" on Human Beta Cell Expansion and Function. 3. To Synthesize Modified Harmalogs with Chemical Linkers That Allow Both Retention of Bioactivity and Conjugation to Beta Cell-Targeting Ligands. We believe these studies are highly significant because they document that adult human beta cells can be induced to proliferate at therapeutically relevant rates using small molecule approaches; they will define the molecular mechanism of action of the harmalog class of compounds; and, because they explore novel methodologies to target these effective regenerative compounds to the human beta cell.