6R3S

CRYSTAL STRUCTURE OF CDK8-CycC IN COMPLEX WITH COMPOUND 1

Summary for 6R3S

• Entry DOI: 10.2210/pdb6r3s/pdb
• Descriptor: Cyclin-dependent kinase 8, Cyclin-C, 6-[5-chloranyl-4-[(1~{S})-1-oxidanylethyl]pyridin-3-yl]-3,4-dihydro-2~{H}-1,8-naphthyridine-1-carboxamide, ... (6 entities in total)
• Functional Keywords: kinase, cell cycle
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 81348.94

Authors

Boettcher, J. (deposition date: 2019-03-21, release date: 2020-04-08, Last modification date: 2024-05-15)

Primary citation

Hofmann, M.H.,Mani, R.,Engelhardt, H.,Impagnatiello, M.A.,Carotta, S.,Kerenyi, M.,Lorenzo-Herrero, S.,Bottcher, J.,Scharn, D.,Arnhof, H.,Zoephel, A.,Schnitzer, R.,Gerstberger, T.,Sanderson, M.P.,Rajgolikar, G.,Goswami, S.,Vasu, S.,Ettmayer, P.,Gonzalez, S.,Pearson, M.,McConnell, D.B.,Kraut, N.,Muthusamy, N.,Moll, J.
Selective and Potent CDK8/19 Inhibitors Enhance NK-Cell Activity and Promote Tumor Surveillance.
Mol.Cancer Ther., 19:1018-1030, 2020

PubMed Abstract: Natural killer (NK) cells play a pivotal role in controlling cancer. Multiple extracellular receptors and internal signaling nodes tightly regulate NK activation. Cyclin-dependent kinases of the mediator complex (CDK8 and CDK19) were described as a signaling intermediates in NK cells. Here, we report for the first time the development and use of CDK8/19 inhibitors to suppress phosphorylation of STAT1 in NK cells and to augment the production of the cytolytic molecules perforin and granzyme B (GZMB). Functionally, this resulted in enhanced NK-cell-mediated lysis of primary leukemia cells. Treatment with the CDK8/19 inhibitor BI-1347 increased the response rate and survival of mice bearing melanoma and breast cancer xenografts. In addition, CDK8/19 inhibition augmented the antitumoral activity of anti-PD-1 antibody and SMAC mimetic therapy, both agents that promote T-cell-mediated antitumor immunity. Treatment with the SMAC mimetic compound BI-8382 resulted in an increased number of NK cells infiltrating EMT6 tumors. Combination of the CDK8/19 inhibitor BI-1347, which augments the amount of degranulation enzymes, with the SMAC mimetic BI-8382 resulted in increased survival of mice carrying the EMT6 breast cancer model. The observed survival benefit was dependent on an intermittent treatment schedule of BI-1347, suggesting the importance of circumventing a hyporesponsive state of NK cells. These results suggest that CDK8/19 inhibitors can be combined with modulators of the adaptive immune system to inhibit the growth of solid tumors, independent of their activity on cancer cells, but rather through promoting NK-cell function.

PubMed: 32024684
DOI: 10.1158/1535-7163.MCT-19-0789

Experimental method

X-RAY DIFFRACTION (2.19 Å)