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5-Methoxybenzothiophene-2-Carboxamides as Inhibitors of Clk1/4: Optimization of Selectivity and Cellular Potency
| Content Provider | MDPI |
|---|---|
| Author | ElHady, Ahmed K. El-Gamil, Dalia S. Chen, Po-Jen Hwang, Tsong-Long Abadi, Ashraf H. Abdel-Halim, Mohammad Engel, Matthias |
| Copyright Year | 2021 |
| Description | : 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 10 b (cell-free IC50 = 12.7 nM), which was four times more selective for Clk1 over Clk2 than the previously published flagship compound 1b. Moreover, 10 b 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. |
| Starting Page | 1001 |
| e-ISSN | 14203049 |
| DOI | 10.3390/molecules26041001 |
| Journal | Molecules |
| Issue Number | 4 |
| Volume Number | 26 |
| Language | English |
| Publisher | MDPI |
| Publisher Date | 2021-02-13 |
| Access Restriction | Open |
| Subject Keyword | Molecules Medicinal Chemistry Clk1 Inhibitor Pre-mrna Splicing Anticancer |
| Content Type | Text |
| Resource Type | Article |
