5-Methoxybenzothiophene-2-Carboxamides as Inhibitors of Clk1/4: Optimization of Selectivity and Cellular Potency

• Published in: Molecules (Basel, Switzerland) Switzerland), 2021-02, Vol.26 (4), p.1001
• Main Authors: ElHady, Ahmed K, El-Gamil, Dalia S, Chen, Po-Jen, Hwang, Tsong-Long, Abadi, Ashraf H, Abdel-Halim, Mohammad, Engel, Matthias
• Format: Article
• Language: English
• Subjects: anticancer; Cell Line, Tumor; Cell Proliferation - drug effects; Clk1 inhibitor; Humans; Models, Molecular; pre-mRNA splicing; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - chemistry; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - chemistry; Substrate Specificity - drug effects; Thiophenes - chemistry; Thiophenes - pharmacology
• ISSN: 1420-3049; 1420-3049
• 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.