Research towards selective inhibition of the CLK3 kinase
Vinay Kumar Singh, Frédéric Justaud, Dabbugoddu Brahmaiah, Nangunoori Sampath Kumar, Blandine Baratte, Thomas Robert, Stéphane Bach, Chada Raji Reddy, Nicolas Levoin, René L Grée
TL;DR
Scientists designed a new molecule that selectively inhibits the CLK3 kinase, which was previously difficult to target.
Contribution
A selective CLK3 inhibitor (VS-77) was developed by exploiting a unique lysine residue found only in CLK3.
Findings
CLK3 has a unique lysine 241 not present in other CLK isoforms.
VS-77 shows significant affinity for CLK3 with an IC50 of 0.3 μM.
VS-77 acts as a pan-inhibitor for the CLK family.
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 (DB18) previously established with a very low activity on CLK3 into a derivative VS-77 which has now a significant affinity toward CLK3 (IC50 = 0.3 μM). Thus, VS-77 appears as a…
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Taxonomy
TopicsChronic Lymphocytic Leukemia Research · Monoclonal and Polyclonal Antibodies Research · Click Chemistry and Applications