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- Title
5-Methoxybenzothiophene-2-Carboxamides as Inhibitors of Clk1/4: Optimization of Selectivity and Cellular Potency.
- Authors
ElHady, Ahmed K.; El-Gamil, Dalia S.; Chen, Po-Jen; Hwang, Tsong-Long; Abadi, Ashraf H.; Abdel-Halim, Mohammad; Engel, Matthias; Collina, Simona; Trabocchi, Andrea
- Abstract
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.
- Subjects
STRUCTURE-activity relationships; CANCER treatment; LEAD compounds; BIOLOGY
- Publication
Molecules, 2021, Vol 26, Issue 4, p1001
- ISSN
1420-3049
- Publication type
Article
- DOI
10.3390/molecules26041001