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. 2018 Dec 26;10(2):76–90. doi: 10.1080/21541264.2018.1556915

Table 1.

Mediator kinase inhibitors as chemical probes Data listed are for CDK8, but similar results are reported for CDK19 unless otherwise stated. All compounds are reversible inhibitors (i.e. non-covalent) and bind competitively with ATP. Each compound has varying levels of off-target effects and the extent of off-target kinase inhibition (i.e. kinases other than CDK8 or CDK19) was tested more rigorously with some compounds compared with others.

Name structure IC50a other data REF
BRD6989 graphic file with name ktrn-10-02-1556915-i001.gif 500nM
in vitro kinase w/CDK8-CCNC 		selective for CDK8 vs. CDK19 49
CCT251545 graphic file with name ktrn-10-02-1556915-i002.gif 5nM
in vitro kinase w/
CDK8-CCNC 		Kd = 3.8nM
(CDK8-CCNC)
IC50 = 65nM
(luciferase reporter)
PDB: 5BNJ		 122
CCT251921 graphic file with name ktrn-10-02-1556915-i003.gif 2.3nM
Lanthascreen or reporter displacement
(CDK8-CCNC) 		IC50 ~ 20 nM
(luciferase reporter)
PDB: 5HBJ		 153
compound 2b graphic file with name ktrn-10-02-1556915-i004.gif 1.8nM
Lanthascreen or reporter displacement
(CDK8-CCNC) 		GI50 = 2nM+
(many lines tested)
IC50 ~ 10nM
(luciferase reporter)		 123
compound 18 graphic file with name ktrn-10-02-1556915-i005.gif 10nM
Reporter displacement
53nM
Lanthascreen
(CDK8-CCNC) 		IC50 = 65nM
(luciferase reporter)		 154
compound 20 graphic file with name ktrn-10-02-1556915-i006.gif 17.4nM
Lanthascreen
(CDK8-CCNC) 		IC50 = 6.5nM
(luciferase reporter)
PDB: 5HVY		 155
compound 25 graphic file with name ktrn-10-02-1556915-i007.gif 2.6nM
Lanthascreen or reporter displacement
(CDK8-CCNC) 		IC50 = 6.5nM
(luciferase reporter)
PDB: 5IDN		 156
compound 32 graphic file with name ktrn-10-02-1556915-i008.gif 1.5nM
assay method unclear 		GI50 = 5.4µM*
(HCT116)
selective for CDK8 vs. CDK19		 71
compound 51 graphic file with name ktrn-10-02-1556915-i009.gif 5.1nM
Lanthascreen or reporter displacement
(CDK8-CCNC) 		IC50 = 7.2nM
(luciferase reporter)		 157
cortistatin A graphic file with name ktrn-10-02-1556915-i010.gif 12nM
in vitro kinase w/
CDK8 module#
100µM ATP		 Kd = 0.2nM
(CDK8-CCNC)
GI50 = 5nM
(MOLM-14)
PDB: 4CRL		 48
SEL120-34A graphic file with name ktrn-10-02-1556915-i011.gif 4.4nM
in vitro kinase w/
CDK8-CCNC
10µM ATP		 Kd = 3nM
(CDK8-CCNC)
GI50 ~ 12nM
(SKNO-1)		 158
senexin A graphic file with name ktrn-10-02-1556915-i012.gif 280nM
in vitro kinase w/
CDK8-CCNC 		Kd ~ 800nM
(CDK8-CCNC)		 159
sorafenib graphic file with name ktrn-10-02-1556915-i013.gif 32.5nM
Lanthascreen
(CDK8-CCNC) 		Kd = 100nM
(CDK8-CCNC)
PDB: 3RGF		 155
160

aThe IC50 results determined from kinase assays will be dependent on ATP concentration, with higher [ATP] yielding higher IC50 values. [ATP] used in the assays is noted if reported.

bOther compounds with similar activity were tested in this study.

*In this study, the GI50 was determined to be due to an off-target effect based upon studies in CDK8 and/or CDK19 knockout cell lines.

#CDK8 module = CDK8, CCNC, MED12, MED13