Issue 1, 2025

Design, synthesis, and structure–activity relationship studies of 6H-benzo[b]indeno[1,2-d]thiophen-6-one derivatives as DYRK1A/CLK1/CLK4/haspin inhibitors

Abstract

A series of sulfur-containing tetracycles was designed and evaluated for their ability to inhibit protein kinase DYRK1A, a target known to have several potential therapeutic applications including cancers, Down syndrome or Alzheimer's disease. Our medicinal chemistry strategy relied on the design of new compounds using ring contraction/isosteric replacement and constrained analogy of known DYRK1A inhibitors, thus resulting in their DYRK1A inhibitory activity enhancement. Whereas a good inhibitory effect of targeted DYRK1A protein was observed for 5-hydroxy compounds 4i–k (IC50 = 35–116 nM) and the 5-methoxy derivative 4e (IC50 = 52 nM), a fairly good selectivity towards its known DYRK1B off-target was observed for 4k. In addition, the most active compound 4k, having an ATP-competitive mechanism of action, proved to be also a potent inhibitor of CLK1/CLK4 (IC50 = 20 and 26 nM) and, to a lesser extent, of haspin (IC50 = 76 nM) kinases. In silico docking studies within the DYRK1A, CLK1/CLK4 and haspin ATP binding sites were carried out to understand the interactions of our tetracyclic derivatives 4 with these targets. Antiproliferative activities on U87/U373 glioblastoma cell lines of the most potent compound 4k showed a moderate effect (IC50 values between 33 and 46 μM). Microsomal stabilities of the designed compounds 4a–m were also investigated, showing great disparities, depending on benzo[b]thiophene ring 5-substitution.

Graphical abstract: Design, synthesis, and structure–activity relationship studies of 6H-benzo[b]indeno[1,2-d]thiophen-6-one derivatives as DYRK1A/CLK1/CLK4/haspin inhibitors

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Article information

Article type
Research Article
Submitted
13 Jul 2024
Accepted
06 Sep 2024
First published
17 Oct 2024
This article is Open Access
Creative Commons BY-NC license

RSC Med. Chem., 2025,16, 179-199

Design, synthesis, and structure–activity relationship studies of 6H-benzo[b]indeno[1,2-d]thiophen-6-one derivatives as DYRK1A/CLK1/CLK4/haspin inhibitors

A. Faouzi, A. Arnaud, F. Hallé, J. Roussel, M. Aymard, V. Denavit, C. V. Do, A. Mularoni, M. Salah, A. ElHady, T. Pham, A. Bancet, M. Le Borgne, R. Terreux, R. Barret, M. Engel and T. Lomberget, RSC Med. Chem., 2025, 16, 179 DOI: 10.1039/D4MD00537F

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