Techniques: Tool compounds for probing cyclin dependent kinase 8 (CDK8)- and cyclin dependent kinase 19 (CDK19; CDC2L6)-dependent tumor growth
TECHNOLOGY: Tool compounds
A series of 3,4,5-trisubstituted pyridine analogs that inhibit CDK8 and CDK19 could be used as tool compounds for investigating the role of the kinases in cancer. Chemical synthesis, in vitro testing and structural analyses of 3,4,5-trisubstituted pyridine analogs identified several compounds that bound CDK8 and CDK19 with Kd values of 14-102 nM and had greater than 100-fold selectivity for CDK8 and CDK19 over 291 other kinases. In three human colorectal cancer cell lines, each compound decreased phosphorylation of targets of CDK8 and CDK19, and levels of CDK8- and CDK19-dependent gene expression, compared with vehicle. In mouse models of breast and colorectal cancers, each compound decreased tumor growth. Next steps could include using the compounds to probe the role of CDK8 and CDK19 in other tumor models. ...