Structure Activity Relationship Studies around DB18, a Potent and Selective Inhibitor of CLK Kinases

Three series of our lead CLK1 inhibitor DB18 have been designed, synthetized and tested against CLKs and DYRK1A kinases. Their cytotoxicity was subsequently measured on seven representative cancer cell lines. Guided by docking experiments, we focused on the less constrained part of the scaffold, and showed that drastically different substituents can be tolerated here. This work ended with the discovery of another promising derivative 12g, with IC50 = 0.004 mu M in the inhibition of HsCLK1 and IC50 = 3.94 mu M for the inhibition of HsDYRK1A. The SAR results are discussed in the light of extensive molecular modeling analyses. Finally, a kinome scan (463 human kinases) confirmed the outstanding selectivity of our lead compound DB18, suggesting that this scaffold is of prominent interest for selective CLK inhibitors. Altogether, these results pave the way for the development of inhibitors with novel selectivities in this family of kinases.

Automated summary

Three series of CLK1 inhibitors were designed, synthesized, and tested against CLKs and DYRK1A kinases. A promising derivative 12g was discovered, showing significant inhibition activity against HsCLK1 and HsDYRK1A. Molecular modeling and kinome scan analysis further supported these results, suggesting the potential for developing selective inhibitors in this kinase family.