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

Three series of our lead CLK1 inhibitor 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 µM in the inhibition of HsCLK1 and IC₅₀ = 3.94 µM 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 , 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.