靶向细胞分裂周期蛋白 2 样（Clk）和双特异性酪氨酸磷酸化调节激酶（Dyrk）的小分子嘧啶抑制剂：化学探针 ML315 的研发。
Small-molecule pyrimidine inhibitors of the cdc2-like (Clk) and dual specificity tyrosine phosphorylation-regulated (Dyrk) kinases: development of chemical probe ML315.
机构信息
University of Kansas Specialized Chemistry Center, University of Kansas, Lawrence, KS 66047, USA.
出版信息
Bioorg Med Chem Lett. 2013 Jun 15;23(12):3654-61. doi: 10.1016/j.bmcl.2013.02.096. Epub 2013 Mar 30.
Abstract
Substituted pyrimidine inhibitors of the Clk and Dyrk kinases have been developed, exploring structure-activity relationships around four different chemotypes. The most potent compounds have low-nanomolar inhibitory activity against Clk1, Clk2, Clk4, Dyrk1A and Dyrk1B. Kinome scans with 442 kinases using agents representing three of the chemotypes show these inhibitors to be highly selective for the Clk and Dyrk families. Further off-target pharmacological evaluation with ML315, the most selective agent, supports this conclusion.
摘要
已开发出取代嘧啶的 Clk 和 Dyrk 激酶抑制剂，探索了围绕四种不同化学型的结构-活性关系。最有效的化合物对 Clk1、Clk2、Clk4、Dyrk1A 和 Dyrk1B 具有低纳摩尔抑制活性。使用代表三种化学型的试剂对 442 种激酶进行激酶组扫描表明，这些抑制剂对 Clk 和 Dyrk 家族具有高度选择性。用最具选择性的试剂 ML315 进行进一步的非靶标药理评估支持这一结论。
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