Molecules (2021)
Update date:2022-08-23
Topics:
Abadi, Ashraf H.
Abdel-Halim, Mohammad
Chen, Po-Jen
El-Gamil, Dalia S.
Elhady, Ahmed K.
Engel, Matthias
Hwang, Tsong-Long
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 10b (cell-free IC50 = 12.7 nM), which was four times more selective for Clk1 over Clk2 than the previously published flagship compound 1b. Moreover, 10b showed an improved growth inhibitory activity with T24 cells (GI50 = 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.
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Doi:10.1021/es034237h
(2004)Doi:10.1246/cl.1997.985
(1997)Doi:10.1021/jo01338a009
(1979)Doi:10.1016/S0040-4039(00)01829-3
(2000)Doi:10.1016/j.cell.2016.08.057
(2016)Doi:10.1006/jcat.2000.3144
(2001)