Research towards selective inhibition of the CLK3 kinase

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 the mRNA splicing process. Among the four isoforms of CLKs, CLK3 is the one for which the biological roles are less 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 residue to design inhibitors with increased affinity towards this kinase as compared to the three other isoforms CLK1, CLK2, and CLK4. Based on this observation, we have been able to transform a molecule (<b>DB18</b>) previously established with a very low activity on CLK3 into a derivative <b>VS-77</b> which has now a significant affinity toward CLK3 (IC<sub>50</sub> = 0.3 μM). Thus, <b>VS-77</b> appears as a new pan-inhibitor of the CLK family.

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Publication Details

Journal
Beilstein Journal of Organic Chemistry
Published
2025-10-24
DOI
https://doi.org/10.3762/bjoc.21.172
Primary Topic
Chronic Lymphocytic Leukemia Research
Type
article
Field-Weighted Citation Impact
0.00

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article

Research towards selective inhibition of the CLK3 kinase

Chada Raji Reddy, Stéphane Bach, Thomas Robert, Nangunoori Sampath Kumar et al.
Beilstein Journal of Organic Chemistry
Chronic Lymphocytic Leukemia Research
article

Research towards selective inhibition of the CLK3 kinase

Chada Raji Reddy, Stéphane Bach, Thomas Robert, Nangunoori Sampath Kumar, D. K. Singh, Nicolas Levoin, Blandine Baratte, Frédéric Justaud, Dabbugoddu Brahmaiah, René Grée
article en

Abstract

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 the mRNA splicing process. Among the four isoforms of CLKs, CLK3 is the one for which the biological roles are less 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 residue to design inhibitors with increased affinity towards this kinase as compared to the three other isoforms CLK1, CLK2, and CLK4. Based on this observation, we have been able to transform a molecule (<b>DB18</b>) previously established with a very low activity on CLK3 into a derivative <b>VS-77</b> which has now a significant affinity toward CLK3 (IC<sub>50</sub> = 0.3 μM). Thus, <b>VS-77</b> appears as a new pan-inhibitor of the CLK family.

Beilstein Journal of Organic ChemistryVol. 21
Centre National de la Recherche Scientifique (FR), Station Biologique de Roscoff (FR), Sorbonne Université (FR), Laboratoire de Biologie Intégrative des Modèles Marins (FR), Institut des Sciences Chimiques de Rennes (FR), Suven Life Sciences (India) (IN), Bharat Immunologicals and Biologicals Corporation (India) (IN), Bioprojet (France) (FR), Indian Institute of Chemical Technology (IN), Université de Rennes (FR)
Infrastructures en Biologie Santé et Agronomie, Ligue Contre le Cancer, Conseil Régional de Bretagne, Centre National de la Recherche Scientifique, Cancéropôle Grand Ouest, Sorbonne Université, Science and Engineering Research Board
Openalex Percentile: Top 58%
Chronic Lymphocytic Leukemia Research
DOIOpen Access PDFOpenAlex
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