1026335-73-8Relevant articles and documents
Development of a Potent, Specific CDK8 Kinase Inhibitor Which Phenocopies CDK8/19 Knockout Cells
Koehler, Michael F. T.,Bergeron, Philippe,Blackwood, Elizabeth M.,Bowman, Krista,Clark, Kevin R.,Firestein, Ron,Kiefer, James R.,Maskos, Klaus,McCleland, Mark L.,Orren, Linda,Salphati, Laurent,Schmidt, Steve,Schneider, Elisabeth V.,Wu, Jiansheng,Beresini, Maureen H.
supporting information, p. 223 - 228 (2016/03/22)
Beginning with promiscuous COT inhibitors, which were found to inhibit CDK8, a series of 6-aza-benzothiophene containing compounds were developed into potent, selective CDK8 inhibitors. When cocrystallized with CDK8 and cyclin C, these compounds exhibit an unusual binding mode, making a single hydrogen bond to the hinge residue A100, a second to K252, and a key cation-πinteraction with R356. Structure-based drug design resulted in tool compounds 13 and 32, which are highly potent, kinase selective, permeable compounds with a free fraction >2% and no measurable efflux. Despite these attractive properties, these compounds exhibit weak antiproliferative activity in the HCT-116 colon cancer cell line. Further examination of the activity of 32 in this cell line revealed that the compound reduced phosphorylation of the known CDK8 substrate STAT1 in a manner identical to a CDK8 knockout clone, illustrating the complex effects of inhibition of CDK8 kinase activity in proliferation in these cells.
