CDK8 inhibitor | BI-1347
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Highlights
Cyclin-dependent kinase 8 (CDK8) is a Mediator complex-associated transcriptional regulator. The Mediator complex is a multiprotein assembly containing up to 30 subunits that consist of four modules each: head, middle, tail and CDK/cyclin and serves as a hub for diverse signaling pathways to regulate gene expression.2 In addition CDK8 inhibition escalates the native activities of Natural Killer cells (NK cells), promoting their tumor surveillance and cytotoxicity.3
BI-1347 is a selective inhibitor of CDK8/cyclinC with an IC50 of 1 nM. BI-1347 with its good DMPK profile showed tumor growth inhibition in an in vivo xenograft model. Together with the also available structurally similar negative control BI-1374, the probe BI-1347 can serve as an excellent small molecule tool inhibitor for testing biological hypotheses in vitro and in vivo.
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Target information
CDK8 and its closely related paralog CDK19 are transcription-regulating cyclin C–dependent kinases. CDK8 and CDK19 are components of the Mediator complex, which provides a link between transcriptional regulators, the RNA polymerase II (Pol II) transcription machinery and gene-specific transcription.4
CDK8 and CDK19 form the kinase module of the Mediator complex along with MED12 and MED13. Recently, several subunits have been implicated in a growing number of human diseases including developmental disorders and cancer. Most evidence has been gathered for the kinase module subunit CDK8, which has been linked to colon and pancreatic cancer and was also investigated as a potential target in cancer therapy.2
CDK8 in complex with inhibitor BI-1374 (X-ray structure solved at Boehringer Ingelheim)
In vitro Activity
BI-1347 is a potent and selective CDK8 inhibitor with an IC50 of 1 nM.
In vitro activity table
|
Probe name |
BI-1347 |
BI-1374 |
|
MW [Da] |
356 |
346 |
|
CDK8/cyclinC inhibition (IC50) [nM] |
1 |
671 |
|
Inhibition of pSTAT S727 in NK-92 cells (IC50) [nM] |
3 |
>10,000 |
|
Secretion of Perforin in NK-92 cells (EC50) [nM] |
10 |
n.d. |
|
Inhibition of proliferation in MV-4-11b cells (IC50) [nM] |
7 |
n.d. |
|
Inhibition of proliferation in NK-92 cells (IC50) [nM] |
>10,000 |
n.d. |
In vitro DMPK parameters
In vitro DMPK parameters table
|
Probe name |
BI-1347 |
BI-1374 |
|
Solubility FaSSIF / FeSSIF [µg/ml] |
11 / 280 |
n.d. |
|
CACO permeability [*10-6 cm/s] |
95 |
n.d. |
|
CACO efflux ratio |
1.1 |
n.d. |
|
Human hepatocyte clearance [%QH] |
17 |
n.d. |
|
Plasma protein binding 10% FCS [%] |
64 |
n.d. |
|
Plasma protein binding human [%] |
98 |
n.d. |
In vivo DMPK parameters
In vivo DMPK parameters of BI-1347 in mouse and rat
|
Species |
mouse |
rat |
|
Dose i.v. / p.o. [mg/kg] |
1 / 10 |
1 / 3 |
|
CL [%QH] |
15 |
14 |
|
Mean residence time after iv dose (l/kg) |
0.6 |
0.7 |
|
F [%] |
93 |
69 |
|
Vss [l/kg] |
0.5 |
0.4 |
Negative control
The compound BI-1374 can be used as an in vitro negative control (CDK8 IC50 = 671 nM)
BI-1374, negative control
Selectivity
Extensive external screens available (also see supplementary data):
Invitrogen® panel: 369 kinases screened @ 10 µM
Selected IC50 measured @ Invitrogen®:
CDK8 IC50 = 1.5 nM; CDK11 IC50 = 1.7 nM; MLCK IC50 = 531 nM; AURKB IC50 = 809 nM; FLT3 IC50 = 1360 nM; ICK IC50 = 2390 nM; STK16 IC50 = 3550 nM
Cerep® External screen covering 44 targets: @ 10 µM
Selectivity data available
|
Probe name |
BI-1347 |
|
Cerep® |
Yes |
|
Eurofins-Panlabs® |
No |
|
Invitrogen® |
Yes |
|
DiscoverX® |
No |
|
Dundee |
No |
Co-crystal structure of the BI probe compound and the target protein
Exists (not released to PDB)
reference molecules
CCT251545, SEL120-34A
Summary
BI-1347 is a selective nanomolar CDK8 inhibitor, suitable for testing biological hypotheses in vitro and also in vivo.
Supplementary data
References
Development of selective and potent CDK8 inhibitors that increase NK cell activity, which translates in tumor surveillance [abstract]
Marco H. Hofmann, Harald Engelhardt, Sebastian Carotta, Heribert Arnhof, Dirk Scharn, Marc Kerenyi, Moritz Mayer, Gerhard Gmaschitz, Georg Egger, Christian Engelhardt, Michael Sanderson, Maria A. Impagnatiello, Renate Schnitzer, Mark Pearson, Darryl McConnell, Norbert Kraut and Jürgen Moll
Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4630.
Pan-Cancer Analysis of the Mediator Complex Transcriptome Identifies CDK19 and CDK8 as Therapeutic Targets in Advanced Prostate Cancer
Johannes Bragelmann, Niklas Klumper, Anne Offermann, Anne von Massenhausen, Diana Bohm, Mario Deng, Angela Queisser,Christine Sanders, Isabella Syring, Axel S. Merseburger, Wenzel Vogel, Elisabeth Sievers, Ignacija Vlasic, Jessica Carlsson, Ove Andren, Peter Brossart, Stefan Duensing, Maria A. Svensson, Zaki Shaikhibrahim, Jutta Kirfel and Sven Perner
Clin Cancer Res, 2016;23(7):1829-1840.
Targeting NK Cells for Anticancer Immunotherapy: Clinical and Preclinical Approaches
Sebastian Carotta
Front. Immunol. 2016;7:1-10.
A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease
Trevor Dale, Paul A Clarke, Christina Esdar, Dennis Waalboer, Olajumoke Adeniji-Popoola, Maria-Jesus Ortiz-Ruiz, Aurélie Mallinger, Rahul S Samant, Paul Czodrowski, Djordje Musil, Daniel Schwarz, Klaus Schneider, Mark Stubbs, Ken Ewan, Elizabeth Fraser, Robert TePoele, Will Court, Gary Box, Melanie Valenti, Alexis de Haven Brandon, Sharon Gowan, Felix Rohdich, Florence Raynaud, Richard Schneider, Oliver Poeschke, Andree Blaukat, Paul Workman, Kai Schiemann, Suzanne A Eccles, Dirk Wienke & Julian Blagg
Nat. Chem. Biol. 2015;9:206–209.
