Aché Laboratórios Farmacêuticos S.A., Guarulhos, SP 07034-904, Brazil.
Centro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), Universidade Estadual de Campinas (UNICAMP), Campinas, SP 13083-875, Brazil.
Bioorg Med Chem Lett. 2022 Jul 15;68:128764. doi: 10.1016/j.bmcl.2022.128764. Epub 2022 May 2.
The discovery of potent and selective inhibitors for understudied kinases can provide relevant pharmacological tools to illuminate their biological functions. DYRK1A and DYRK1B are protein kinases linked to chronic human diseases. Current DYRK1A/DYRK1B inhibitors also antagonize the function of related protein kinases, such as CDC2-like kinases (CLK1, CLK2, CLK4) and DYRK2. Here, we reveal narrow spectrum dual inhibitors of DYRK1A and DYRK1B based on a benzothiophene scaffold. Compound optimization exploited structural differences in the ATP-binding sites of the DYRK1 kinases and resulted in the discovery of 3n, a potent and cell-permeable DYRK1A/DYRK1B inhibitor. This compound has a different scaffold and a narrower off-target profile compared to current DYRK1A/DYRK1B inhibitors. We expect the benzothiophene derivatives described here to aid establishing DYRK1A/DYRK1B cellular functions and their role in human pathologies.
针对研究较少的激酶开发出有效且选择性的抑制剂，可以为阐明其生物学功能提供相关的药理学工具。DYRK1A 和 DYRK1B 是与慢性人类疾病相关的蛋白激酶。目前的 DYRK1A/DYRK1B 抑制剂也会拮抗相关蛋白激酶的功能，如 CDC2 样激酶（CLK1、CLK2、CLK4）和 DYRK2。在这里，我们基于苯并噻吩骨架揭示了 DYRK1A 和 DYRK1B 的窄谱双重抑制剂。通过优化化合物，利用 DYRK1 激酶的 ATP 结合位点的结构差异，发现了具有高活性和细胞通透性的 DYRK1A/DYRK1B 抑制剂 3n。与目前的 DYRK1A/DYRK1B 抑制剂相比，该化合物具有不同的骨架和更窄的脱靶谱。我们期望这里描述的苯并噻吩衍生物能够帮助确定 DYRK1A/DYRK1B 的细胞功能及其在人类疾病中的作用。
