International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai, China.
Bioorg Med Chem Lett. 2012 Jan 1;22(1):168-71. doi: 10.1016/j.bmcl.2011.11.043. Epub 2011 Nov 18.
In this study, six novel dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) inhibitors with IC(50) values ranging from 1.51 to 88.13 μM were successfully identified through virtual screening and in vitro plus cell based bioassay. Compound 5 with IC(50) value of 1.51 μM is the most potent hit against DYRK1A in vitro, while compound 3 exhibited the most potent activity in cultured cells. The inhibition mechanism was explored by molecular docking approach. This study may provide a start point for further mechanism based study as well as discovery of drug candidate against Down syndrome (DS).
在这项研究中，通过虚拟筛选和基于体外和细胞的生物测定，成功鉴定出了六种新型双特异性酪氨酸磷酸化调节激酶 1A（DYRK1A）抑制剂，其 IC50 值范围为 1.51-88.13 μM。化合物 5 的 IC50 值为 1.51 μM，是体外对 DYRK1A 最有效的化合物，而化合物 3 在培养细胞中表现出最强的活性。通过分子对接方法探索了抑制机制。这项研究可能为进一步的基于机制的研究以及发现针对唐氏综合征（DS）的药物候选物提供一个起点。
