Pharmacological Validation of IRE1 for Diabetes Mellitus

描述（由申请人提供）：分泌和跨膜蛋白的结构成熟和折叠始于内质网（ER）。这些过程由ER驻留的蛋白质折叠机制催化，所述蛋白质折叠机制包括分子伴侣、氧化还原酶和其他蛋白质修饰酶。如果对分泌途径的需求超过容量，这些ER驻留活动变得不堪重负，导致客户蛋白以未折叠形式积累。在这种“ER应激”的情况下，受影响的细胞变性和死亡的风险增加。越来越多的证据表明内质网（ER）应激在人类糖尿病（1型和2型）的病因和发病机制中起作用。未折叠蛋白反应（UPR）是一系列试图纠正ER应激的信号通路，已被定义并广泛研究。在内质网应激下，UPR启动转录和翻译变化，促进适应。然而，不可补救的ER应激水平导致这些适应性措施结束，而是迎来了一个终端UPR，驱动细胞向功能障碍和疾病状态，往往导致程序性细胞死亡。我们已经确定了主UPR调节器-IRE 1-作为终端UPR的关键守门人。IRE 1是一种双功能激酶/核糖核酸内切酶（RNase），具有决定细胞命运的不同输出。该项目的总体目标是推进新型激酶抑制剂，用于控制细胞进入终末UPR的关键靶点的早期药理学验证，从而开发用于人类糖尿病疾病修饰的治疗前先导化合物。

DESCRIPTION (provided by applicant): Structural maturation and folding of secretory and transmembrane proteins begins in the endoplasmic reticulum (ER). These processes are catalyzed by an ER-resident protein-folding machinery comprising molecular chaperones, oxidoreductases, and other protein-modifying enzymes. If demand on the secretory pathway exceeds capacity, these ER-resident activities become overwhelmed, leading client proteins to accumulate in unfolded forms. During such instances of 'ER stress,' affected cells are at increased risk for degeneration and death. Accruing evidence implicates endoplasmic reticulum (ER) stress in the etiology and pathogenesis of diabetes mellitus (both types 1 and 2) in humans. The unfolded protein response (UPR), a collection of signaling pathways that attempt to correct ER stress, has been defined and extensively studied. Under ER stress, the UPR sets in motion transcriptional and translational changes that promote adaptation. However, irremediable levels of ER stress cause these adaptive measures to end, and instead usher in a terminal UPR that drives cells toward dysfunctional and diseased states, often leading to programmed cell death. We have identified the master UPR regulator-IRE1�-as a key gatekeeper of the terminal UPR. IRE1� is a bifunctional kinase/endoribonuclease (RNase) that has divergent outputs that determine cell fate. The overall goal of this project is to advance novel kinase inhibitors for early-stage pharmacological validation of this key target controlling entry of cells into the terminal UPR, and to thereby develop pre-therapeutic lead compounds for disease modification in human diabetes mellitus.