Research towards selective inhibition of the CLK3 kinase
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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 (IC 50 = 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.