- 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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p. 223 - 228
(2016/03/22)
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- Selective inhibition of ICAM-1 and E-selectin expression in human endothelial cells. 2. Aryl modifications of 4-(Aryloxy)thieno[2,3-c]pyridines with fine-tuning at C-2 carbamides
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The elevated expression of cell adhesion molecules (CAMs) on the lumenal surface of vascular endothelial cells is a critical early event in the complex inflammatory process. The adhesive interactions of these CAMs that include E-selectin, ICAM-1, and VCAM
- Zhu,Arendsen,Gunawardana,Boyd,Stewart,Fry,Cool,Kifle,Schaefer,Meuth,Marsh,Kempf-Grote,Kilgannon,Gallatin,Okasinski
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p. 3469 - 3487
(2007/10/03)
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- Cell adhesion-inhibiting antiinflammatory compounds
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Compounds having Formula I are useful for treating inflammation. Also disclosed are pharmaceutical compositions comprising compounds of Formula I, and methods of inhibiting/treating inflammatory diseases in a mammal.
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