6TPA

CDK8/CyclinC in complex with drug ETP-50775

Summary for 6TPA

• Entry DOI: 10.2210/pdb6tpa/pdb
• Descriptor: Cyclin-dependent kinase 8, Cyclin-C, 1-[4-chloranyl-3-(trifluoromethyl)phenyl]-3-(5-oxidanylidene-6-pyridin-4-yl-pyrido[2,3-b][1,5]benzoxazepin-9-yl)urea, ... (6 entities in total)
• Functional Keywords: cell division kinase inhibitor, cell cycle
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 81881.39

Authors

Munoz, I.G.,Pastor, J.,Martinez, S. (deposition date: 2019-12-12, release date: 2020-11-18, Last modification date: 2024-01-24)

Primary citation

Martinez-Gonzalez, S.,Garcia, A.B.,Albarran, M.I.,Cebria, A.,Amezquita-Alves, A.,Garcia-Campos, F.J.,Martinez-Gago, J.,Martinez-Torrecuadrada, J.,Munoz, I.,Blanco-Aparicio, C.,Pastor, J.
Pyrido[2,3-b][1,5]benzoxazepin-5(6H)-one derivatives as CDK8 inhibitors.
Eur.J.Med.Chem., 201:112443-112443, 2020

PubMed Abstract: CDK8 is a cyclin-dependent kinase that forms part of the mediator complex, and modulates the transcriptional output from distinct transcription factors involved in oncogenic control. Overexpression of CDK8 has been observed in various cancers, representing a potential target for developing novel CDK8 inhibitors in cancer therapeutics. In the course of our investigations to discover new CDK8 inhibitors, we designed and synthesized tricyclic pyrido[2,3-b][1,5]benzoxazepin-5(6H)-one derivatives, by introduction of chemical complexity in the multi-kinase inhibitor Sorafenib taking into account the flexibility of the P-loop motif of CDK8 protein observed after analysis of structural information of co-crystallized CDK8 inhibitors. In vitro evaluation of the inhibitory activity of the prepared compounds against CDK8 led us to identify compound 2 as the most potent inhibitor of the series (IC = 8.25 nM). Co-crystal studies and the remarkable selectivity profile of compound 2 are presented. Compound 2 showed moderate reduction of phosphorylation of CDK8 substrate STAT1 in cells, in line with other reported Type II CDK8 inhibitors. We propose herein an alternative to find a potential therapeutic use for this chemical series.

PubMed: 32599324
DOI: 10.1016/j.ejmech.2020.112443

Experimental method

X-RAY DIFFRACTION (2.8 Å)