5CEI

Crystal structure of CDK8:Cyclin C complex with compound 22

Summary for 5CEI

• Entry DOI: 10.2210/pdb5cei/pdb
• Related: 4G6L
• Descriptor: Cyclin-dependent kinase 8, Cyclin-C, 1,2-ETHANEDIOL, ... (6 entities in total)
• Functional Keywords: kinase, inhibitor, cdk8, cyclin dependent kinase, cyclin, transcription-transferase-inhibitor complex, transcription/transferase/inhibitor
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus : P49336 P24863
• Total number of polymer chains: 2
• Total formula weight: 82044.96

Authors

Kiefer, J.R.,Schneider, E.V.,Maskos, K.,Koehler, M.F.T. (deposition date: 2015-07-06, release date: 2016-02-10, Last modification date: 2024-03-06)

Primary citation

Koehler, M.F.,Bergeron, P.,Blackwood, E.M.,Bowman, K.,Clark, K.R.,Firestein, R.,Kiefer, J.R.,Maskos, K.,McCleland, M.L.,Orren, L.,Salphati, L.,Schmidt, S.,Schneider, E.V.,Wu, J.,Beresini, M.H.
Development of a Potent, Specific CDK8 Kinase Inhibitor Which Phenocopies CDK8/19 Knockout Cells.
Acs Med.Chem.Lett., 7:223-228, 2016

PubMed Abstract: Beginning with promiscuous COT inhibitors, which were found to inhibit CDK8, a series of 6-aza-benzothiophene containing compounds were developed into potent, selective CDK8 inhibitors. When cocrystallized with CDK8 and cyclin C, these compounds exhibit an unusual binding mode, making a single hydrogen bond to the hinge residue A100, a second to K252, and a key cation-π interaction with R356. Structure-based drug design resulted in tool compounds 13 and 32, which are highly potent, kinase selective, permeable compounds with a free fraction >2% and no measurable efflux. Despite these attractive properties, these compounds exhibit weak antiproliferative activity in the HCT-116 colon cancer cell line. Further examination of the activity of 32 in this cell line revealed that the compound reduced phosphorylation of the known CDK8 substrate STAT1 in a manner identical to a CDK8 knockout clone, illustrating the complex effects of inhibition of CDK8 kinase activity in proliferation in these cells.

PubMed: 26985305
DOI: 10.1021/acsmedchemlett.5b00278

Experimental method

X-RAY DIFFRACTION (2.24 Å)