Perturbation of endoplasmic reticulum (ER) proteostasis is associated with impairment of cellular function in diverse diseases, especially the function of pancreatic β cells in type 2 diabetes. Restoration of ER proteostasis by small molecules shows therapeutic promise for type 2 diabetes. Here, using cell-based screening, we report identification of a chemical chaperone-like small molecule, KM04794, that alleviates ER stress. KM04794 prevented protein aggregation and cell death caused by ER stressors and a mutant insulin protein. We also found that this compound increased intracellular and secreted insulin levels in pancreatic β cells. Chemical biology and biochemical approaches revealed that the compound accumulated in the ER and interacted directly with the ER molecular chaperone BiP. Our data show that this corrector of ER proteostasis can enhance insulin storage and pancreatic β cell function.

内质网 (ER) 蛋白质稳态的扰动与多种疾病中细胞功能的损害有关，尤其是 2 型糖尿病中胰腺 β 细胞的功能。通过小分子恢复 ER 蛋白质稳态显示出对 2 型糖尿病的治疗前景。在这里，使用基于细胞的筛选，我们报告了一种化学伴侣样小分子 KM04794 的鉴定，它可以减轻 ER 压力。KM04794 可防止由 ER 应激源和突变胰岛素蛋白引起的蛋白质聚集和细胞死亡。我们还发现这种化合物增加了胰腺 β 细胞的细胞内和分泌的胰岛素水平。化学生物学和生化方法表明，该化合物在 ER 中积累并与 ER 分子伴侣 BiP 直接相互作用。