A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease

• DOI: 10.1038/nchembio.1952
• Publication Date: 2015-10-26T15:23:46Z
• Authors: Trevor Dale; Paul A Clarke; Christina Esdar; Dennis Waalboer; Olajumoke Adeniji...; Maria-Jesus Ortiz...; Aurélie Mallinger; Rahul S Samant; Paul Czodrowski; Djordje Musil; Daniel Schwarz; Klaus Schneider; Mark Stubbs; Ken Ewan; Elizabeth Fraser; Robert TePoele; Will Court; Gary Box; Melanie Valenti; Alexis de Haven B...; Sharon Gowan; Felix Rohdich; Florence Raynaud; Richard Schneider; Oliver Poeschke; Andree Blaukat; Paul Workman; Kai Schiemann; Suzanne A Eccles; Dirk Wienke; Julian Blagg
• Keywords: Models, Molecular; 0301 basic medicine; 570; Tumor; Molecular Structure; Pyridines; 610; Molecular; Cyclin-Dependent Kinase 8; Article; Cyclin-Dependent Kinases; Cell Line; 3. Good health; 03 medical and health sciences; Models; Cell Line, Tumor; Molecular Probes; Colonic Neoplasms; Humans; Spiro Compounds; Protein Kinase Inhibitors

There is unmet need for chemical tools to explore the role of the Mediator complex in human pathologies ranging from cancer to cardiovascular disease. Here we determine that CCT251545, a small-molecule inhibitor of the WNT pathway discovered through cell-based screening, is a potent and selective chemical probe for the human Mediator complex-associated protein kinases CDK8 and CDK19 with >100-fold selectivity over 291 other kinases. X-ray crystallography demonstrates a type 1 binding mode involving insertion of the CDK8 C terminus into the ligand binding site. In contrast to type II inhibitors of CDK8 and CDK19, CCT251545 displays potent cell-based activity. We show that CCT251545 and close analogs alter WNT pathway-regulated gene expression and other on-target effects of modulating CDK8 and CDK19, including expression of genes regulated by STAT1. Consistent with this, we find that phosphorylation of STAT1(SER727) is a biomarker of CDK8 kinase activity in vitro and in vivo. Finally, we demonstrate in vivo activity of CCT251545 in WNT-dependent tumors.