New CDK8 inhibitors as potential anti-leukemic agents – Design, synthesisand biological evaluation
Peer reviewed, Journal article
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OriginalversjonSolum, E. J., Hansen, T. V., Aesoy, R. & Herfindal, L. (2020). New CDK8 inhibitors as potential anti-leukemic agents – Design, synthesisand biological evaluation. Bioorganic & Medicinal Chemistry, 28(10): 115461. doi: 10.1016/j.bmc.2020.115461
Cyclin-dependent kinase 8 (CDK8) plays a vital role in regulating cell transcription either through its association with the mediator complex or by the phosphorylation of transcription factors. CDK8-mediated activation of oncogenes has proved to be important in a variety of cancer types including hematological malignancies. We have designed and synthesized a series of new synthetic steroids. The compounds were evaluated as CDK8 inhibitors in vitro. The three most potent compounds exhibit Kd-values towards CDK8 in the low nanomolar range (3.5–18 nM). Furthermore, the compounds displayed selectivity for CDK8 in a panel of 465 different kinases. The cell studies indicated a selectivity to kill AML-cancer cell lines compared to normal cell lines.