Background:

Senexin A is a CDK8 inhibitor with an IC50 of 280 nM. CDK19|0.31 μM (Kd)|CDK8|0.83 μM (Kd)

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. The induction of transcription factor EGR1 upon serum starvation, followed by readdition of serum, is strongly inhibited by Senexin A in HT1080 cells. Senexin A inhibits only p21-induced transcription but not other biological effects of p21. Senexin A also decreases the expression of many secreted tumor-promoting factors in doxorubicin-treated wild-type HCT116 cells[1].

Five daily treatment of Senexin A fully reverses tumor-promoting effect of chemotherapy. Senexin A shows no detectable toxicity and no significant effects on body weight, organ weights, or blood cell counts in C57BL/6 mice during the treatment. This effect of doxorubicin treatment is completely abolished, however, when doxorubicin injection is followed by administration of Senexin A. Senexin A treatment strongly improves the response of A549/MEF tumors to doxorubicin[1].

[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.