CDK8 inhibitor
BI-1347
BI-1347 is a potent and selective Cyclin-dependent kinase 8 (CDK8) /cyclinC inhibitor with an IC50 of 1 nM. With its good DMPK profile, this compound is suitable for both in vitro and in vivo experiments and may be a useful tool to explore the role of CDK8 in human diseases such as cancer. In an in vivo xenograft model, BI-1347 treatment resulted in tumor growth inhibition.
More information
CDK8 and its closely related paralog CDK19 are transcription-regulating cyclin C–dependent kinases. CDK8 and CDK19 are components of the Mediator complex, a multiprotein assembly containing up to 30 subunits organized in four modules: head, middle, tail and CDK/Cyclin. The Mediator complex serves as a hub for diverse signaling pathways and provides a link between transcriptional regulators, the RNA polymerase II (Pol II) transcription machinery and gene-specific transcription2.
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 therapy2. CDK8 inhibition was shown to escalate the native activities of Natural Killer cells (NK cells), promoting their tumor surveillance and cytotoxicity3.
CDK8 in complex with inhibitor BI-1374 (X-ray structure solved at Boehringer Ingelheim)
BI-1347 is a potent and selective CDK8 inhibitor with an IC50 of 1 nM.
| Probe name | BI-1347 | BI-1374 |
| MW [Da]a | 356.4 | 346.4 |
| 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. |
aFor the salt form you will get, please refer to the label on the vial and for the molecular weight of the salt, please refer to the FAQs
| Probe name | BI-1347 | BI-1374 |
| logD @ pH 11 | 2.4 | 0.4 |
| Solubilitiy @ pH 7 [µg/mL] | <1.0 | >84 |
| Solubility FaSSIF / FeSSIF [µg/ml] | 11 / 280 | n.a. |
| Caco-2 permeability AB [*10-6 cm/s] | 95 | n.a. |
| Caco-2 efflux ratio | 1.1 | n.a. |
| Human hepatocyte clearance [% QH] | 17 | n.a. |
| Plasma Protein Binding 10% FCS [%] | 64 | n.a. |
| Plasma Protein Binding human [%] | 98 | n.a. |
| BI-1347 | MOUSEA | RATB |
|---|---|---|
| Clearance [% QH] | 15 | 14 |
| Mean residence time after i.v. dose (L/kg) | 0.6 | 0.7 |
| F [%] | 93 | 69 |
| Vss [L/kg] | 0.5 | 0.4 |
ai.v. dose: 1 mg/kg; p.o. dose: 10 mg/kg
bi.v. dose: 1 mg/kg; p.o. dose: 3 mg/kg
The compound BI-1374 can be used as an in vitro negative control (CDK8 IC50 = 671 nM).
BI-1374, negative control
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
Eurofins Safety Panel 44™ External screen covering 44 targets: @ 10 µM
| SELECTIVITY DATA AVILABLE | BI-1347 | BI-1374 |
SafetyScreen44™ with kind support of  | Yes | Yes |
| Invitrogen® | Yes | No |
| DiscoverX® | No | No |
| Dundee | No | No |
Download selectivity data:
BI-1347_selectivityData_0.xlsx
BI-1374_selectivityData.xlsx
CCT251545, SEL120-34A
BI-1347 is a selective nanomolar CDK8 inhibitor, suitable for testing biological hypotheses in vitro and also in vivo.
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.
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.
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.
When you plan a publication, please use the following acknowledgement:
BI-1347 was kindly provided by Boehringer Ingelheim via its open innovation platform opnMe, available at https://www.opnme.com.