Université Clermont Auvergne, CNRS, SIGMA Clermont, ICCF, F-63000, Clermont-Ferrand, France; Carthage University, Laboratory of Organic and Analytical Chemistry (ISEFC), Tunis, Tunisia.
Université Clermont Auvergne, CNRS, SIGMA Clermont, ICCF, F-63000, Clermont-Ferrand, France.
Eur J Med Chem. 2019 Mar 15;166:304-317. doi: 10.1016/j.ejmech.2019.01.052. Epub 2019 Jan 26.
Cdc2-like kinase 1 (CLK1) and dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) are involved in the regulation of alternative pre-mRNA splicing. Dysregulation of this process has been linked to cancer progression and neurodegenerative diseases, making CLK1 and DYRK1A important therapeutic targets. Here we describe the synthesis of new pyrido[3,4-g]quinazoline derivatives and the evaluation of the inhibitory potencies of these compounds toward CDK5, CK1, GSK3, CLK1 and DYRK1A. Introduction of aminoalkylamino groups at the 2-position resulted in several compounds with low nanomolar affinity and selective inhibition of CLK1 and/or DYRK1A. Their evaluation on several immortalized or cancerous cell lines showed varying degree of cell viability reduction. Co-crystal structures of CLK1 with two of the most potent compounds revealed two alternative binding modes of the pyrido[3,4-g]quinazoline scaffold that can be exploited for future inhibitor design.
Cdc2 样激酶 1（CLK1）和双特异性酪氨酸磷酸化调节激酶 1A（DYRK1A）参与调节可变剪接前体 mRNA。该过程的失调与癌症进展和神经退行性疾病有关，使得 CLK1 和 DYRK1A 成为重要的治疗靶标。在这里，我们描述了新的吡啶并[3,4-g]喹唑啉衍生物的合成，并评价了这些化合物对 CDK5、CK1、GSK3、CLK1 和 DYRK1A 的抑制活性。在 2 位引入氨基烷基氨基基团得到了几个具有低纳摩尔亲和力和选择性抑制 CLK1 和/或 DYRK1A 的化合物。对几种永生化或癌细胞系的评价显示，它们具有不同程度的细胞活力降低。与两种最有效的化合物的 CLK1 共晶结构揭示了吡啶并[3,4-g]喹唑啉支架的两种替代结合模式，可用于未来的抑制剂设计。
