Dyrk Inhibitors for Human Beta Cell Expansion

 描述(申请人提供)：1型和2型糖尿病都是由于胰岛β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人类β细胞替换和/或再生的新药和工具。这已被证明是困难的，因为成年人类β细胞难以参与细胞周期进程。最近，我们设计并进行了由两个小分子文库组成的独特的高通量筛选(HTS)，一个是2000年的FDA化合物文库，另一个是100,000个化合物文库，并发现了一种新的有效的小分子骆驼蓬碱，它能够以接近治疗性人类β细胞复制所需的速度激活小鼠、大鼠和人类的β细胞复制。我们还鉴定了其他与骆驼蓬碱有相同结构和功能特征的化合物，并将它们称为“骆驼蓬”。正在进行的构效研究表明，这些化合物使用的共同途径是钙调神经磷酸酶-NFAT-DYRK1A途径，但其他途径和细胞内靶点仍然是可能的。至于广泛的贝塔细胞生物学领域，将哈马罗格定位于贝塔细胞是具有挑战性的。因此，在本申请中，我们召集了一支由经验丰富的β细胞生物学家和药物化学家组成的团队，以追求三个具体目标：1.充分确定Harmalog对人类Beta细胞增殖的作用机制。2.活体观察Harmalog对人β细胞增殖和功能的影响。3.合成具有化学连接物的修饰的Harmalog，该连接物既能保留生物活性，又能与Beta细胞靶向配体结合。我们认为这些研究意义重大，因为它们证明了使用小分子方法可以诱导成人人类β细胞以治疗相关的速度增殖；它们将定义harmarog类化合物的分子作用机制；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.