Dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is the most promising target for diabetes treatment by promoting -cell proliferation. The desmethylbellidifolin (DMB) as a DYRK1A inhibitor could facilitate -cell proliferation and . However, DMB has the problem of weak binding affinity to DYRK1A, which means that continuous high concentration administration of DMB is effective for the diabetes. In order to solve this problem, we designed and synthesized a series of DMB-based proteolysis targeting chimeras (PROTACs) by taking advantage of the property of PROTAC that induce protein degradation in a cycle-catalytic manner. MDM2-based PROTAC -- was identified as the most active PROTAC molecule. Mechanism research showed that -- formed a ternary complex with DYRK1A and murine double minute 2 (MDM2), and induced the degradation of DYRK1A through the ubiquitin-proteasome system pathway. At a dose much lower than that of DMB, -- still significantly enhanced -cell proliferation by inhibiting transforming growth factor beta (TGF-) and promoting the mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway, which may provide a new strategy for the application of DMB in diabetes.

中文翻译：

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设计、合成和评估第一个用于促进胰腺 β 细胞增殖的 DYRK1A 降解剂

双特异性酪氨酸磷酸化调节激酶 1A (DYRK1A) 通过促进细胞增殖而成为糖尿病治疗最有希望的靶点。desmethylbellidifolin (DMB) 作为 DYRK1A 抑制剂可以促进 细胞增殖和 。然而，DMB存在与DYRK1A结合力弱的问题，这意味着持续高浓度施用DMB对于糖尿病是有效的。为了解决这个问题，我们利用PROTAC以循环催化方式诱导蛋白质降解的特性，设计并合成了一系列基于DMB的蛋白水解靶向嵌合体（PROTAC）。基于 MDM2 的 PROTAC——被确定为最活跃的 PROTAC 分子。机制研究表明——与DYRK1A和鼠双分钟2（MDM2）形成三元复合物，并通过泛素-蛋白酶体系统途径诱导DYRK1A降解。在远低于 DMB 的剂量下，通过抑制转化生长因子 β (TGF-) 和促进丝裂原激活蛋白激酶/细胞外信号调节激酶 (MAPK/ERK) 信号通路，仍然显着增强细胞增殖，这可能为DMB在糖尿病中的应用提供新的策略。