Structure-activity relationship for the folding intermediate-selective inhibition of DYRK1A
Structure-activity relationship for the folding intermediate-selective inhibition of DYRK1A
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DYRK1A 折叠中间选择性抑制的构效关系
DOI：
10.1016/j.ejmech.2021.113948
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发表时间：
2022
影响因子：
6.7
通讯作者：
Kii Isao
中科院分区：
文献类型：
--
作者：
Miyazaki Yuka;Kikuchi Masaki;Umezawa Koji;Descamps Aurelie;Nakamura Daichi;Furuie Gaku;Sumida Tomoe;Saito Kanako;Kimura Ninako;Niwa Takashi;Sumida Yuto;Umehara Takashi;Hosoya Takamitsu;Kii Isao
DYRK1A以分子间方式磷酸化参与神经疾病的蛋白质。同时，在DYRK1a的蛋白质折叠过程中，一种过渡性的折叠中间体催化分子内的自磷酸化，这是“一次性”启动和稳定所需的。在我们以前的研究中，我们发现了一个命名为FINDY(1)的小分子，它抑制折叠中间体催化的DYRK1A的分子内自磷酸化，但不抑制折叠状态催化的分子间磷酸化。然而，负责这种中间选择性抑制的FINDY(1)的结构特征仍然难以捉摸。在本研究中，根据预测的FINDY(1)在DYRK1AATP口袋中的结合模式，设计并合成了FINDY(1)的结构衍生物。衍生物的定量构效关系(QSAR)表明，对折叠中间体的选择性是由衍生物的疏水基团与口袋入口之间的空间位阻决定的。此外，还发现了一种比FINDY(1)更强的抑制折叠中间体的衍生物3，命名为ASDP-FINDY。虽然dp-FINDY(3)和FINDY(1)一样不抑制折叠状态，但在体外无细胞蛋白质合成实验中，它抑制了DYRK1A的分子内自磷酸化。此外，DP-FINDY(3)使HEK293细胞内源性DYRK1A不稳定。这项研究为DYRK1A的折叠中间体选择性抑制提供了结构上的见解，并扩大了设计激酶抑制剂的化学选择。
DYRK1A phosphorylates proteins involved in neurological disorders in an intermolecular manner. Meanwhile, during the protein folding process of DYRK1A, a transitional folding intermediate catalyzes the intramolecular autophosphorylation required for the “one-off” inceptive activation and stabilization. In our previous study, a small molecule termedFINDY(1) was identified, which inhibits the folding intermediate-catalyzed intramolecular autophosphorylation of DYRK1A but not the folded state-catalyzed intermolecular phosphorylation. However, the structural features ofFINDY(1) responsible for this intermediate-selective inhibition remain elusive. In this study, structural derivatives ofFINDY(1) were designed and synthesized according to its predicted binding mode in the ATP pocket of DYRK1A. Quantitative structure-activity relationship (QSAR) of the derivatives revealed that the selectivity against the folding intermediate is determined by steric hindrance between the bulky hydrophobic moiety of the derivatives and the entrance to the pocket. In addition, a potent derivative3was identified, which inhibited the folding intermediate more strongly thanFINDY(1); it was designated asdp-FINDY. Althoughdp-FINDY(3) did not inhibit the folded state, as well asFINDY(1), it inhibited the intramolecular autophosphorylation of DYRK1A in an in vitro cell-free protein synthesis assay. Furthermore,dp-FINDY(3) destabilized endogenous DYRK1A in HEK293 cells. This study provides structural insights into the folding intermediate-selective inhibition of DYRK1A and expands the chemical options for the design of a kinase inhibitor.