5-Methoxybenzothiophene-2-Carboxamides as Inhibitors of Clk1/4: Optimization of Selectivity and Cellular Potency
Ahmed K ElHady1,2, Dalia S El-Gamil1, Po-Jen Chen3,4
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt.
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.
Insights
New 5-methoxybenzothiophene-2-carboxamide derivatives show high selectivity for Clk1, a promising target in cancer therapy. Compound 10b demonstrates potent inhibition and improved activity against T24 cancer cells.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- CDK-like kinases (Clks) regulate pre-mRNA splicing and are implicated in tumor biology.
- Clk1 and Clk4 are overexpressed in various human tumors, making them potential therapeutic targets.
- Existing Clk1 inhibitors often lack selectivity, exhibiting off-target effects on Clk2, Dyrk1A, and Dyrk1B.
Purpose of the Study:
- To develop novel 5-methoxybenzothiophene-2-carboxamide derivatives with enhanced selectivity for Clk1.
- To identify potent and selective Clk1 inhibitors for potential cancer therapy.
Main Methods:
- Synthesis of new 5-methoxybenzothiophene-2-carboxamide derivatives.
- Evaluation of Clk1 inhibitory activity and selectivity against Clk2, Dyrk1A, and Dyrk1B.
- Assessment of growth inhibitory activity against T24 cancer cells.
- Development of a molecular binding model for Clk1.
Main Results:
- Discovery of compound 10b, a highly selective Clk1 inhibitor (cell-free IC50 = 12.7 nM).
- Compound 10b exhibits four-fold greater selectivity for Clk1 over Clk2 compared to previous lead compounds.
- Compound 10b demonstrates significant growth inhibitory activity against T24 cells (GI50 = 0.43 µM).
- Structure-activity relationships led to a new binding model within the Clk1 ATP pocket.
Conclusions:
- Novel benzothiophene derivatives offer unprecedented selectivity for Clk1.
- Compound 10b represents a promising candidate for further development in Clk1-targeted cancer therapy.
- The established binding model provides insights for future inhibitor design.
More Related Videos
08:49Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
11:44Cellular Membrane Affinity Chromatography Columns to Identify Specialized Plant Metabolites Interacting with Immobilized Tropomyosin Kinase Receptor B
Published on: January 19, 2022
