New CDK8 inhibitors as potential anti-leukemic agents - Design, synthesis and biological evaluation
- Bioorg Med Chem. 2020 May 15;28(10):115461. doi: 10.1016/j.bmc.2020.115461.
- 1. Faculty of Health Sciences, Nord University, 7801 Namsos, Norway; University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway. Electronic address: [email protected].
- 2. University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway.
- 3. Centre for Pharmacy, Department of Clinical Science, University of Bergen, PO Box 7800, N-5007 Bergen, Norway.
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.