A role of Dyrk1A in the progression of Down syndrome–related Alzheimer's disease (AD) is well supported. However, the involvement of Dyrk1A in the pathogenesis of Parkinson's disease (PD) was much less studied, and it is not clear whether it would be promising to test Dyrk1A inhibitors in relevant PD models. Herein, we modified our previously published 1-(6-hydroxybenzo[d]thiazol-2-yl)-3-phenylurea scaffold of Dyrk1A inhibitors to obtain a new series of analogues with higher selectivity for Dyrk1A on the one hand, but also with a novel, additional activity as inhibitors of α-synuclein (α-syn) aggregation, a major pathogenic hallmark of PD. The phenyl acetamide derivative b27 displayed the highest potency against Dyrk1A with an IC₅₀ of 20 nM and high selectivity over closely related kinases. Furthermore, b27 was shown to successfully target intracellular Dyrk1A and to inhibit SF3B1 phosphorylation in HeLa cells with an IC₅₀ of 690 nM. In addition, two compounds among the Dyrk1A inhibitors, b1 and b20, also suppressed the aggregation of α-synuclein (α-syn) oligomers (with IC₅₀ values of 10.5 μM and 7.8 μM, respectively). Both compounds but not the Dyrk1A reference inhibitor harmine protected SH-SY5Y neuroblastoma cells against α-syn–induced cytotoxicity, with b20 exhibiting a higher neuroprotective effect. Compound b1 and harmine were more efficient in protecting SH-SY5Y cells against 6-hydroxydopamine–induced cell death, an effect that was previously correlated to Dyrk1A inactivation in cells but not yet verified using chemical inhibitors. The presented dual inhibitors exhibited a novel activity profile encouraging for further testing in neurodegenerative disease models.

Dyrk1A 在唐氏综合症相关阿尔茨海默病 (AD) 进展中的作用得到了充分支持。然而，Dyrk1A 在帕金森病 (PD) 发病机制中的作用研究较少，并且尚不清楚在相关 PD 模型中测试 Dyrk1A 抑制剂是否有希望。在此，我们修改了之前发表的 Dyrk1A 抑制剂的 1-(6-羟基苯并[ d ]噻唑-2-基)-3-苯基脲支架，以获得一系列新的类似物，一方面对 Dyrk1A 具有更高的选择性，而且还具有作为 α-突触核蛋白 (α-syn) 聚集抑制剂的一种新颖的额外活性，α-突触核蛋白 (α-syn) 聚集是 PD 的主要致病标志。苯基乙酰胺衍生物b27对 Dyrk1A 表现出最高的效力，IC ₅₀为 20 nM，并且对密切相关的激酶具有高选择性。此外， b27在 HeLa 细胞中成功靶向细胞内 Dyrk1A 并抑制 SF3B1 磷酸化，IC ₅₀为 690 nM。此外，Dyrk1A抑制剂中的两种化合物b1和b20也抑制α-突触核蛋白（α-syn）寡聚体的聚集（IC ₅₀值分别为10.5 μM和7.8 μM）。这两种化合物（但 Dyrk1A 参考抑制剂去氢骆驼蓬碱除外）可以保护 SH-SY5Y 神经母细胞瘤细胞免受 α-syn 诱导的细胞毒性，其中b20表现出更高的神经保护作用。化合物b1和去氢骆驼蓬碱在保护 SH-SY5Y 细胞免受 6-羟基多巴胺诱导的细胞死亡方面更有效，这种效应之前被认为与细胞中 Dyrk1A 失活相关，但尚未使用化学抑制剂进行验证。 所提出的双重抑制剂表现出新颖的活性特征，鼓励在神经退行性疾病模型中进行进一步测试。