CDK8 inhibitor | BI-1347

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Target protein: 
CDK8
Probe Name: 
BI-1347
MOLECULAR WEIGHT [DA]: 
356.4
In stock: 
756

Chemical structure

2D structure of BI-1347

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)

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

MOLECULAR WEIGHT OF NEGATIVE CONTROL [DA]: 
346.4

The compound BI-1374 can be used as an in vitro negative control (CDK8 IC50 = 671 nM)

BI-1374, negative control

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

Download selectivity data: 

Co-crystal structure of the BI probe compound and the target protein

Exists (not released to PDB)

reference molecules

CCT251545, SEL120-34A

Summary

Cyclin-dependent kinase 8 (CDK8) is a Mediator complex-associated transcriptional regulator. Mediator 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 escalate 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 compound BI-1374, which can be used as negative control due to much weaker potency BI-1347 can serve as an excellent small molecule inhibitor for testing biological hypotheses like the role of the Mediator complex in human pathologies of as a tool targeting NK cells for anticancer immunotherapy in vitro and in vivo.

Supplementary data

References

  1. Development of selective and potent CDK8 inhibitors that increase NK cell activity, which translates in tumor surveillance [abstract]

    Hofmann M. H., Engelhardt H., Carotta S., Arnhof H., Scharn D., Kerenyi M., Mayer M., Gmaschitz G., Egger G., Engelhardt C., Sanderson M., Impagnatiello M. A., Schnitzer R., Pearson M., McConnell D., Kraut N., Moll J.

    Proceedings of the American Association for Cancer Research Annual Meeting 2017, 2017, Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017, 77(13 Suppl):Abstract nr 4630.

  2. Pan-Cancer Analysis of the Mediator Complex Transcriptome Identifies CDK19 and CDK8 as Therapeutic Targets in Advanced Prostate Cancer

    Brägelmann J., Klümper N., Offermann A., von Mässenhausen A., Böhm D., Deng M., Queisser A., Sanders C., Syring I., Merseburger A. S., Vogel W., Sievers E., Vlasic I., Carlsson J., Andrén O., Brossart P., Duensing S., Svensson M. A., Shaikhibrahim Z., Kirfel J., Perner S.

    Clin Cancer Res, 2016, 23, 1829-1840.

  3. Targeting NK Cells for Anticancer Immunotherapy: Clinical and Preclinical Approaches

    Carotta S.

    Front. Immunol. 2016, 7, 1-10.

  4. A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease

    Dale T., Clarke P. A., Esdar C., Waalboer D., Adeniji-Popoola O., Ortiz-Ruiz M. J., Mallinger A., Samant R. S., Czodrowski P., Musil D., Schwarz D., Schneider K., Stubbs M., Ewan K., Fraser E., TePoele R., Court W., Box G., Valenti M., de Haven Brandon A., Gowan S., Rohdich F., Raynaud F., Schneider R., Poeschke O., Blaukat A., Workman P., Schiemann K., Eccles S. A., Wienke D., Blagg J.

    Nat. Chem. Biol. 2015, 9, 206–209.

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