Research towards selective inhibition of the CLK3 kinase  

chemistry Medicinal and pharmaceutical chemistry Nano- and molecular-scale electronics Nano-biomaterials and bioscience Nanomagnetics Nanomaterials, thin films and nanointerfaces Nanomedicine Nanometrology and nanomechanics Nano-optics Nanopatterning, self-assembly and nanofabrication Nanostructures for energy and sensing applications Natural products chemistry Organo main group chemistry Other nanotechnology (unclassified) Other organic chemistry (unclassified) Photochemistry and photovoltaics Physical organic chemistry Supramolecular chemistry The cdc2-like kinases (CLKs), are a family of kinases that attracted recently the interest of scientists due to their significant biological roles, in particular in the regulation of mRNA splicing process. Among the four isoforms of CLKs, the CLK3 is the one for which the biological roles are less well understood, in part because no selective inhibitor of this challenging kinase has been found to date. Based on structural analysis of the CLKs we have identified the lysine 241, present only in CLK3, as an attractive target to design inhibitors with increased affinity towards this kinase as compared to the three others. Based on this, we have been able to transform a molecule (DB18) previously established with a low activity on CLK3 into a derivative (VS-77) which has now a significant affinity toward this CLK3 kinase (IC50 = 0.3mM). Further, since this compound has kept good activities against the other CLKs, VS-77 can be qualified as a new pan-inhibitor of the CLKs.

Kinases • CLK3 • Quinazolines • Cancer • Triazoles • Molecular modelling | Format: PDF | Size: 1.6 MB | Download | When a peer-reviewed version of this preprint is available, this information will be updated in the information box above. If no peer-reviewed version is available, please cite this preprint using the following information: Singh, V. K.; Justaud, F.; Brahmaiah, D.; Kumar, N. S.; Baratte, B.; Robert, T.; Bach, S.; Reddy, C. R.; Levoin, N.; Grée, R. L. Beilstein Arch. 2025, 202544. doi:10.3762/bxiv.2025.44.v1 Citation data can be downloaded as file using the "Download" button or used for copy/paste from the text window below. Citation data in RIS format can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Zotero. © 2025 Singh et al.; licensee Beilstein-Institut. This is an open access work licensed under the terms of the Beilstein-Institut Open Access License Agreement (https://www.beilstein-archives.org/xiv/terms), which is identical to the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0). The reuse of material under this license requires that the author(s), source and license are credited. Third-party material in this work could be subject to other licenses (typically indicated in the credit line), and in this case, users are required to obtain permission from the license holder to reuse the material.