N-Benzylated 5-Hydroxybenzothiophene-2-carboxamides as Multi-Targeted Clk/Dyrk Inhibitors and Potential Anticancer
Noha Mostafa1,2, Po-Jen Chen3,4, Sarah S Darwish1,5
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt.
Abstract:
Numerous studies have reported that Dyrk1A, Dyrk1B, and Clk1 are overexpressed in multiple cancers, suggesting a role in malignant disease. Here, we introduce a novel class of group-selective kinase inhibitors targeting Dyrk1A, Dyrk1B, and Clk1. This was achieved by modifying our earlier selective Clk1 inhibitors, which were based on the 5-methoxybenzothiophene-2-carboxamide scaffold. By incorporating a 5-hydroxy group, we increased the potential for additional hydrogen bond interactions that broadened the inhibitory effect to include Dyrk1A and Dyrk1B kinases. Within this series, compounds 12 and 17 emerged as the most potent multi-kinase inhibitors against Dyrk1A, Dyrk1B, and Clk1. Furthermore, when assessed against the most closely related kinases also implicated in cancer, the frontrunner compounds revealed additional inhibitory activity against Haspin and Clk2. Compounds 12 and 17 displayed high potency across various cancer cell lines with minimal effect on non-tumor cells. By examining the effect of these inhibitors on cell cycle distribution, compound 17 retained cells in the G2/M phase and induced apoptosis. Compounds 12 and 17 could also increase levels of cleaved caspase-3 and Bax, while decreasing the expression of the antiapoptotic Bcl-2 protein. These findings support the further study and development of these compounds as novel anticancer therapeutics.
Insights
Novel kinase inhibitors targeting Dyrk1A, Dyrk1B, and Clk1 show promise as anticancer therapeutics. Compounds 12 and 17 effectively inhibit cancer cell growth and induce apoptosis with minimal impact on healthy cells.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Dyrk1A, Dyrk1B, and Clk1 kinases are frequently overexpressed in various cancers, indicating their involvement in malignant progression.
- Targeting these kinases presents a potential strategy for developing novel cancer therapies.
Purpose of the Study:
- To design and synthesize a novel class of group-selective kinase inhibitors targeting Dyrk1A, Dyrk1B, and Clk1.
- To evaluate the anticancer potential of these novel inhibitors in cancer cell lines.
Main Methods:
- Modification of existing 5-methoxybenzothiophene-2-carboxamide scaffold to create new inhibitors.
- In vitro kinase inhibition assays to determine potency against Dyrk1A, Dyrk1B, Clk1, and related kinases (Haspin, Clk2).
- Assessment of compound efficacy in various cancer cell lines, including cell cycle analysis and apoptosis induction studies.
Main Results:
- Compounds 12 and 17 demonstrated potent multi-kinase inhibition against Dyrk1A, Dyrk1B, and Clk1.
- These compounds also exhibited inhibitory activity against Haspin and Clk2 kinases.
- Compounds 12 and 17 showed high efficacy in cancer cell lines, inducing G2/M phase arrest, apoptosis, and modulating key apoptotic markers (caspase-3, Bax, Bcl-2) with minimal toxicity to non-tumor cells.
Conclusions:
- Compounds 12 and 17 represent a promising new class of multi-kinase inhibitors with significant anticancer potential.
- These findings warrant further investigation and development of these compounds as novel therapeutic agents for cancer treatment.
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