Discovery of novel pyridine skeleton derivatives as potent CLK2/3 inhibitors

The CLK family plays a crucial role in regulating the transcript splicing, catalyzing the molecular mechanism of spliceosomes. It also regulates the activity or expression of non-spliced proteins by phosphorylating SR proteins. Hence, CLKs are promising therapeutic targets for a variety of diseases, especially in tumors. Several small molecule CLK2/3 inhibitors were under the clinical studies, while most of these molecule possessed N-containing bicyclic heteroaryl as the skeleton. The goal of this work was to introduce a novel skeleton as well as provide structure diversity to the development of CLK2/3 inhibitors. Herein, a series of pyridine derivatives (5a-5h, 6a-6e, and 7a-7g) were designed, synthesized and evaluated. Among them, compound 7c was identified to have good inhibitory activities against both CLK2/3 and proliferation of SW480 tumor cell. Additionally, pharmacokinetic study in mice as well as the stability assay were performed to investigate the druggability of 7c. The good in vitro activity and promising pharmacokinetic properties indicated that the 7c was a reliable lead compound for further development.

CLK2; CLK3; Inhibitor; Small molecule.