Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt.
School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, New Administrative Capital, Cairo 11865, Egypt.
Molecules. 2021 Feb 13;26(4):1001. doi: 10.3390/molecules26041001.
Clks have been shown by recent studies to be promising targets for cancer therapy, as they are considered key regulators in the process of pre-mRNA splicing, which in turn affects every aspect of tumor biology. In particular, Clk1 and -4 are overexpressed in several human tumors. Most of the potent Clk1 inhibitors reported in the literature are non-selective, mainly showing off-target activity towards Clk2, Dyrk1A and Dyrk1B. Herein, we present new 5-methoxybenzothiophene-2-carboxamide derivatives with unprecedented selectivity. In particular, the introduction of a 3,5-difluoro benzyl extension to the methylated amide led to the discovery of compound (cell-free IC = 12.7 nM), which was four times more selective for Clk1 over Clk2 than the previously published flagship compound . Moreover, showed an improved growth inhibitory activity with T24 cells (GI = 0.43 µM). Furthermore, a new binding model in the ATP pocket of Clk1 was developed based on the structure-activity relationships derived from new rigidified analogues.
最近的研究表明，CLK 是癌症治疗的有前途的靶点，因为它们被认为是前体 mRNA 剪接过程中的关键调节剂，而这反过来又影响肿瘤生物学的各个方面。特别是，CLK1 和 -4 在几种人类肿瘤中过度表达。文献中报道的大多数有效的 CLK1 抑制剂是非选择性的，主要对 CLK2、Dyrk1A 和 Dyrk1B 表现出脱靶活性。在此，我们提出了具有前所未有的选择性的新 5-甲氧基苯并噻吩-2-甲酰胺衍生物。特别是，在甲基酰胺上引入 3,5-二氟苄基延伸，发现了化合物 （无细胞 IC = 12.7 nM），它对 Clk1 的选择性比以前发表的旗舰化合物 高四倍。此外，化合物 对 T24 细胞的生长抑制活性（GI = 0.43 µM）也有所提高。此外，根据新的刚性类似物的构效关系，开发了 Clk1 中 ATP 口袋的新结合模型。
