Senexin A is a potent and selective inhibitor of CDK8 and its nearest relative, CDK19 with Kd values of 0.83 μM and 0.31 μM for CDK8 and CDK19 ATP site binding, respectively.
Senexin A is a potent and selective inhibitor of CDK8 and its nearest relative, CDK19 with Kd values of 0.83 μM and 0.31 μM for CDK8 and CDK19 ATP site binding, respectively.
p21 is shown to activate NF-κB–dependent transcription, and Senexin A inhibits p21-stimulated activity of the consensus NF-κB–dependent promoter. Senexin A has no effect on p21 induction by IPTG, on cell growth with or without p21, or on p21-induced senescent phenotype. Senexin A does not affect the inhibition of gene expression by p21 and does not interfere with p21-mediated inhibition of large sets of genes belonging to Gene Ontology (GO) categories of mitosis and DNA replication. Senexin A inhibits only p21-induced transcription but not other biological effects of p21. Senexin A inhibits CDK8 and CDK19 ATP site binding with Kd50 of 0.83 μM and 0.31 μM, respectively and CDK8 kinase activity with IC50 of 0.28 μM. Senexin A inhibits β-catenin–dependent transcription in HCT116 colon carcinoma cells. It does not inhibit ROCK and did not share cortistatin A's strong antiendothelial cell activity[1].
The CDK8/19 inhibitor Senexin A reverses chemotherapy-induced paracrine tumor-promoting activities in vivo and does not inhibit reporter cell growth and showed no detectable toxicity in a mouse study[1].
[1] Porter DC, et al. Proc Natl Acad Sci U S A. 2012, 109(34):13799-804.
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Animal experiment: |
Mice: Senexin A toxicity study is conducted by Taconic in C57BL/6 mice, using five mice per group treated with 20 mg/kg Senexin A or carrier (80% propylene glycol), with five daily i.p. injections. Mice are weighed on days 3 and 6, and killed on day 6. Organ weights are determined for brain, kidney, thymus, spleen, lung, and liver. Terminal blood samples are analyzed to determine the numbers of total white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, and basophils[1]. |
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参考文献: [1]. Porter DC, et al. Cyclin-dependent kinase 8 mediates chemotherapy-induced tumor-promoting paracrine activities. Proc Natl Acad Sci U S A. 2012 Aug 21;109(34):13799-804. |
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