- Development of a Potent, Specific CDK8 Kinase Inhibitor Which Phenocopies CDK8/19 Knockout Cells
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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.
- 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.
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supporting information
p. 223 - 228
(2016/03/22)
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- Discovery of thieno[2,3-c]pyridines as potent COT inhibitors
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Evaluation of hit chemotypes from high throughput screening identified a novel series of 2,4-disubstituted thieno[2,3-c]pyridines as COT kinase inhibitors. Structural modifications exploring SAR at the 2- and 4-positions resulting in inhibitors with improved enzyme potency and cellular activity are disclosed.
- George, Dawn,Friedman, Michael,Allen, Hamish,Argiriadi, Maria,Barberis, Claude,Bischoff, Agnieszka,Clabbers, Anca,Cusack, Kevin,Dixon, Richard,Fix-Stenzel, Shannon,Gordon, Thomas,Janssen, Bernd,Jia, Yong,Moskey, Maria,Quinn, Christopher,Salmeron, Jose-Andres,Wishart, Neil,Woller, Kevin,Yu, Zhengtian
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scheme or table
p. 4952 - 4955
(2009/05/30)
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- KINASE INHIBITORS AS THERAPEUTIC AGENTS
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A compound or pharmaceutically acceptable salts thereof of Formula (I) wherein the substituents are as defined herein, which are useful as kinase inhibitors.
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