ml5b00278_si_001.pdf (1.26 MB)
Development of a Potent, Specific CDK8 Kinase Inhibitor Which Phenocopies CDK8/19 Knockout Cells
journal contribution
posted on 2016-01-06, 00:00 authored by Michael F. T. Koehler, Philippe Bergeron, Elizabeth
M. Blackwood, Krista Bowman, Kevin R. Clark, Ron Firestein, James R. Kiefer, Klaus Maskos, Mark L. McCleland, Linda Orren, Laurent Salphati, Steve Schmidt, Elisabeth
V. Schneider, Jiansheng Wu, Maureen H. BeresiniBeginning 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−π interaction
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.