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 ( DB18 ) previously established with a very low activity on CLK3 into a derivative VS-77 which has now a significant affinity toward CLK3 (IC ₅₀ = 0.3 μM). Thus, VS-77 appears as a new pan-inhibitor of the CLK family.