Senexin A

Description: Senexin A is a novel, potent, selective and ATP site competitive inhibitor of CDK8 and CDK19 with Kd values of 0.83 uM and 0.31 uM for CDK8 and CDK19, respectively. Conventional chemotherapy not only kills tumor cells but also changes gene expression in treatment-damaged tissues, inducing production of multiple tumor-supporting secreted factors. This secretory phenotype was found to be mediated in part by a damage-inducible cell-cycle inhibitor p21 (CDKN1A). Senexin A inhibits damage-induced transcription downstream of p21. Senexin A suppresses damage-induced tumor-promoting paracrine activities of tumor cells and normal fibroblasts and reverses the increase in tumor engraftment and serum mitogenic activity in mice pretreated with a chemotherapeutic drug. Senexin A also increases the efficacy of chemotherapy against xenografts formed by tumor cell/fibroblast mixtures. Microarray data analysis revealed striking correlations between CDK8 expression and poor survival in breast and ovarian cancers. CDK8 inhibition by Senexin A offers a promising approach to increasing the efficacy of cancer chemotherapy.

References: Proc Natl Acad Sci U S A. 2012 Aug 21; 109(34):13799-804.