CDK8

Summary

CDK8 (cyclin dependent kinase 8, HGNC:1779) is a protein-coding gene on chromosome 13q12.13, encoding Cyclin-dependent kinase 8 (P49336). Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes.

This gene encodes a member of the cyclin-dependent protein kinase (CDK) family. CDK family members are known to be important regulators of cell cycle progression. This kinase and its regulatory subunit, cyclin C, are components of the Mediator transcriptional regulatory complex, involved in both transcriptional activation and repression by phosphorylation of the carboxy-terminal domain of the largest subunit of RNA polymerase II. This kinase regulates transcription by targeting the cyclin-dependent kinase 7 subunits of the general transcription initiation factor IIH, thus providing a link between the Mediator complex and the basal transcription machinery. Multiple pseudogenes of this gene have been identified. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 1024 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual developmental disorder with hypotonia and behavioral abnormalities (Definitive, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 115 total — 10 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 26
• Druggable target: yes — 23 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001260

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1779
Approved symbol	CDK8
Name	cyclin dependent kinase 8
Location	13q12.13
Locus type	gene with protein product
Status	Approved
Aliases	K35
Ensembl gene	ENSG00000132964
Ensembl biotype	protein_coding
OMIM	603184
Entrez	1024

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 13 protein_coding, 4 protein_coding_CDS_not_defined, 2 retained_intron, 2 nonsense_mediated_decay

ENST00000381527, ENST00000465820, ENST00000477277, ENST00000480323, ENST00000536792, ENST00000625988, ENST00000700501, ENST00000700502, ENST00000700503, ENST00000700504, ENST00000700505, ENST00000869726, ENST00000869727, ENST00000869728, ENST00000869729, ENST00000869730, ENST00000869731, ENST00000869732, ENST00000869733, ENST00000869734, ENST00000923333

RefSeq mRNA: 3 — MANE Select: NM_001260 NM_001260, NM_001318368, NM_001346501

CCDS: CCDS9317

Canonical transcript exons

ENST00000381527 — 13 exons

Exon	Start	End
ENSE00001489094	26254129	26254769
ENSE00003495682	26401269	26401347
ENSE00003532430	26337567	26337642
ENSE00003601261	26396285	26396354
ENSE00003633174	26353740	26353880
ENSE00003633797	26401466	26401624
ENSE00003636628	26349072	26349182
ENSE00003652143	26400453	26400550
ENSE00003684408	26393367	26393510
ENSE00003685781	26397153	26397225
ENSE00003688592	26403956	26405238
ENSE00003979987	26382814	26382871
ENSE00003979992	26385211	26385342

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 95.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.9832 / max 265.8515, expressed in 1805 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
134488	10.3812	1786
134489	6.6020	1700

Top tissues by expression

294 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	95.76	gold quality
buccal mucosa cell	CL:0002336	95.20	gold quality
secondary oocyte	CL:0000655	94.82	gold quality
oocyte	CL:0000023	93.08	gold quality
sperm	CL:0000019	92.68	gold quality
parietal pleura	UBERON:0002400	90.74	gold quality
endothelial cell	CL:0000115	90.48	gold quality
muscle layer of sigmoid colon	UBERON:0035805	90.47	gold quality
visceral pleura	UBERON:0002401	90.40	gold quality
amniotic fluid	UBERON:0000173	90.23	gold quality
esophagus squamous epithelium	UBERON:0006920	89.59	gold quality
pleura	UBERON:0000977	89.32	gold quality
cortical plate	UBERON:0005343	89.27	gold quality
sigmoid colon	UBERON:0001159	89.15	gold quality
jejunal mucosa	UBERON:0000399	89.14	gold quality
male germ cell	CL:0000015	88.99	gold quality
ganglionic eminence	UBERON:0004023	87.10	gold quality
Brodmann (1909) area 23	UBERON:0013554	86.97	gold quality
palpebral conjunctiva	UBERON:0001812	86.92	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.87	gold quality
epithelium of esophagus	UBERON:0001976	86.67	gold quality
tibia	UBERON:0000979	86.46	gold quality
colon	UBERON:0001155	86.35	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.26	gold quality
choroid plexus epithelium	UBERON:0003911	86.22	gold quality
gingival epithelium	UBERON:0001949	86.19	gold quality
large intestine	UBERON:0000059	86.10	gold quality
jejunum	UBERON:0002115	85.89	gold quality
embryo	UBERON:0000922	85.73	gold quality
cerebellar cortex	UBERON:0002129	85.47	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.08

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

5 targets.

Target	Regulation
ANKRD37
HES1	Activation
MAGI1
STC2
UHMK1

Upstream regulators (CollecTRI, top): MYC, PARP1, STAT1

miRNA regulators (miRDB)

167 targeting CDK8, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420

Literature-anchored findings (GeneRIF, showing 40)

• CDK8 play positive roles in transcriptional activation. (PMID:17212659)
• RNA interference experiments demonstrate that CDK8 functions as a coactivator within the p53 transcriptional program. (PMID:17612495)
• Within T/G-Mediator, cdk8 phosphorylates serine-10 on histone H3, which in turn stimulates H3K14 acetylation by GCN5L within the complex. (PMID:18418385)
• by retaining RB1 and amplifying CDK8, colorectal tumour cells select conditions that collectively suppress E2F1 and enhance the activity of beta-catenin (PMID:18794899)
• CDK8 kinase activity was necessary for beta-catenin-driven transformation and for expression of several beta-catenin transcriptional targets (PMID:18794900)
• Med12–but not Med13–is essential for activating the CDK8 kinase. (PMID:19047373)
• Med12 and Med13 are critical for human CDK8 subcomplex -dependent repression, whereas CDK8 kinase activity is not (PMID:19240132)
• Overexpression of CDK8 is associated with beta-catenin activation and colon cancer. (PMID:19790197)
• The authors show, using a human tumor cell line, that CDK8 is a positive regulator of genes within the serum response network, including several members of the activator protein 1 and early growth response family of oncogenic transcription factors. (PMID:20098423)
• plays a role in mechanisms of transcriptional regulation upon protein phosphorylation. (review) (PMID:20408451)
• CDK8 may identify a subset of colon cancer patients with poor prognosis. (PMID:20514474)
• The Walleye dermal sarcoma virus cyclin functions as a structural ortholog of cyclin C in spite of its limited amino acid sequence identity with C cyclins or with any known cyclins and activates Cdk8 and Cdk3. (PMID:21067790)
• significant inverse correlation between mH2A and CDK8 expression levels exists in melanoma patient samples (PMID:21179167)
• beta-catenin expression was suppressed by CDK8 interference in the gastric adenocarcinoma cell lines. (PMID:21344156)
• 2.2-A crystal structure of CDK8/CycC in complex with sorafenib; the CDK8 activation loop appears not to be phosphorylated. Based on the structure, we discuss an alternate mode of CDK8 activation to the general CDK activation by T-loop phosphorylation (PMID:21806996)
• Microarrays identified target genes for each CDK, and we selected six genes: two target genes of CDK8, two target genes of CDK19 and two genes that were targets for both. (PMID:22117896)
• we identify a role for the CDK8 oncogene in regulating tumor differentiation and stem cell pluripotency (PMID:22345154)
• Retroviral cyclin enhances cyclin-dependent kinase-8 activity. (PMID:22379099)
• Cyclin-dependent kinase 8 mediates chemotherapy-induced tumor-promoting paracrine activities (PMID:22869755)
• The phosphorylation of S375 by CDK8 regulates E2F1 ability to repress transcription of beta-catenin/TCF-dependent genes, as well as activation of E2F1-dependent genes. (PMID:22945643)
• CDK8 is a key regulator of STAT1 and antiviral responses. (PMID:23352233)
• results show a reverse correlation between CDK8 levels and several key features of the endometrial cancer cells, including cell proliferation, migration and invasion as well as tumor formation in vivo (PMID:23454913)
• Authors found that interaction of the CDK8 kinase module with Mediator’s middle module interferes with C-terminal domain-dependent RNAPII binding to a previously unknown middle-module CTD-binding site and with the holoenzyme formation process. (PMID:23563140)
• analysis of the structure-kinetic relationship of the cyclin-dependent kinase 8 (CDK8)/cyclin C (CycC) complex (PMID:23630251)
• Study reports that HIF1A employs a specific variant of the Mediator complex to stimulate RNAPII elongation; the Mediator-associated kinase CDK8, but not the paralog CDK19, is required for induction of many HIF1A target genes. (PMID:23746844)
• CDK8 and CDK19, individually interact with PRMT5 and WDR77, and their interactions with PRMT5 cause transcriptional repression of C/EBPbeta target genes. (PMID:23749998)
• Here, loss of CDK8 suppressed the reduced mRNA expression and RNAPII occupancy levels of CTD truncation mutants. (PMID:24009531)
• CDK8 regulates the transcription factors turnover, C-terminal domain phosphorylation, and regulates the activator or repressor functions. (Review) (PMID:24139904)
• Cdk8 is required for stress-induced Mdv1-Dnm1 interaction and mitochondrial fragmentation. (PMID:24439911)
• Cancer-mediated CDK8 point mutations (D173A and D189N) change the binding pattern of cdk8 to its partner, CycC. (PMID:24754906)
• A novel transcriptional repression mechanism of hMED18 mediated by hCDK8 and further a novel positive role of free CDK/cyclin module in transcriptional activation is described. (PMID:24840924)
• Suggest that miR-107 plays a key role in cisplatin resistance by targeting the CDK8 protein in non small cell lung cancer cells. (PMID:25400821)
• The Skp2-mH2A1-CDK8 axis has a critical role in breast cancer development via dysregulation of the G2/M transition, polyploidy, cell growth dysregulation, and loss of tumor suppression. (PMID:25818643)
• Data suggest that, during neurogenesis, Mediator complex cyclin-dependent kinases (CDK8, CDK19) interact directly with PRC2 (polycomb repressive complex 2) subunit EZH2 (enhancer of zeste homolog 2), as well as SUZ12 (suppressor of zeste 12 homolog). (PMID:26002960)
• Current state of the art confirms that further development of CDK8 inhibitors will translate into targeted therapies in oncology (PMID:26006748)
• our results suggest that mTORC1 activation in NAFLD and insulin resistance results in down-regulation of the CDK8-CycC complex and elevation of lipogenic protein expression. (PMID:26042770)
• Data suggest that MED13, MED12, CDK8 and cyclin C (CycC) comprise a four-subunit “kinase” module of the Mediator complex that functions as a major ingress of oncogenic and developmental signaling/gene expression in humans. [REVIEW] (PMID:26182352)
• miR-101 is a potent tumor repressor that directly represses CDK8 expression (PMID:26286725)
• our data provided evidence that CDK-8 played a significant role in colon cancer hepatic metastasis by regulating the Wnt/beta-catenin signal pathway (PMID:26349978)
• Mediator-associated kinases CDK8 and CDK19 restrain increased activation of key super-enhancer-associated genes in acute myeloid leukaemia (AML) cells (PMID:26416749)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cdk8	ENSDARG00000016496
mus_musculus	Cdk8	ENSMUSG00000029635
rattus_norvegicus	Cdk8	ENSRNOG00000039819

Paralogs (26): CDKL3 (ENSG00000006837), CDKL5 (ENSG00000008086), CDK11A (ENSG00000008128), CDK14 (ENSG00000058091), CDK17 (ENSG00000059758), CDK13 (ENSG00000065883), CDKL1 (ENSG00000100490), CDK16 (ENSG00000102225), CDK6 (ENSG00000105810), PRP4K (ENSG00000112739), CDK18 (ENSG00000117266), CDK2 (ENSG00000123374), CDK7 (ENSG00000134058), CDK4 (ENSG00000135446), CDK9 (ENSG00000136807), CDK15 (ENSG00000138395), CDKL2 (ENSG00000138769), CDK19 (ENSG00000155111), CDK20 (ENSG00000156345), CDK5 (ENSG00000164885), CDK12 (ENSG00000167258), CDK1 (ENSG00000170312), CDK10 (ENSG00000185324), CDKL4 (ENSG00000205111), CDK11B (ENSG00000248333), CDK3 (ENSG00000250506)

Protein

Protein identifiers

Cyclin-dependent kinase 8 — P49336 (reviewed: P49336)

Alternative names: Cell division protein kinase 8, Mediator complex subunit CDK8, Mediator of RNA polymerase II transcription subunit CDK8, Protein kinase K35

All UniProt accessions (5): P49336, A0A0D9SEP3, A0A0D9SFZ2, A0A8V8TQY4, F5H6D4

UniProt curated annotations — full annotation on UniProt →

Function. Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional pre-initiation complex with RNA polymerase II and the general transcription factors. Phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex. Phosphorylates CCNH leading to down-regulation of the TFIIH complex and transcriptional repression. Recruited through interaction with MAML1 to hyperphosphorylate the intracellular domain of NOTCH, leading to its degradation.

Subunit / interactions. Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. The cylin/CDK pair formed by CCNC/CDK8 also associates with the large subunit of RNA polymerase II. Interacts with CTNNB1, GLI3 and MAML1.

Subcellular location. Nucleus.

Disease relevance. Intellectual developmental disorder with hypotonia and behavioral abnormalities (IDDHBA) [MIM:618748] An autosomal dominant neurodevelopmental disorder with onset in infancy. IDDHBA is characterized by hypotonia, global developmental delay, learning disability, and behavioral abnormalities, such as autistic features and attention deficit-hyperactivity disorder. Additional variable features may include non-specific facial dysmorphism, congenital heart defects, ocular anomalies, and poor feeding. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P49336-1	1	yes
P49336-2	2

RefSeq proteins (3): NP_001251, NP_001305297, NP_001333430 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR050108	CDK	Family

Pfam: PF00069

Enzyme classification (BRENDA):

• EC 2.7.11.22 — cyclin-dependent kinase (BRENDA: 49 organisms, 441 substrates, 555 inhibitors, 8 Km, 4 kcat entries)
• EC 2.7.11.23 — [RNA-polymerase]-subunit kinase (BRENDA: 12 organisms, 155 substrates, 47 inhibitors, 15 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.01–0.06	6
ADAQHATPPKKKRKVEDPKDF	0.046–0.521	2
ATP	0.0052–0.017	2
HEPTA-SIX PEPTIDE	0.189–0.2	2
L-ARG-HEPTA PEPTIDE	0.212–0.243	2
FIN1	0.003	1
PKTPKKAKKL	0.0029	1
CTD-CONTAINING FUSION PROTEIN	0.0002	1
GTP	0.18	1
SYNTHETIC PEPTIDE	0.15	1
[DNA-DIRECTED RNA POLYMERASE]	0.0001	1

Catalyzed reactions (Rhea), 3 shown:

• [DNA-directed RNA polymerase] + ATP = phospho-[DNA-directed RNA polymerase] + ADP + H(+) (RHEA:10216)
• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (56 total): helix 18, sequence variant 10, strand 10, turn 6, compositionally biased region 3, region of interest 2, binding site 2, chain 1, domain 1, splice variant 1, mutagenesis site 1, active site 1

Structure

Experimental structures (PDB)

36 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5XS2	X-RAY DIFFRACTION	2.04
4F6U	X-RAY DIFFRACTION	2.1
9H8S	X-RAY DIFFRACTION	2.16
5ICP	X-RAY DIFFRACTION	2.18
6R3S	X-RAY DIFFRACTION	2.19
6Y0A	X-RAY DIFFRACTION	2.19
3RGF	X-RAY DIFFRACTION	2.2
4F7S	X-RAY DIFFRACTION	2.2
5CEI	X-RAY DIFFRACTION	2.24
5IDN	X-RAY DIFFRACTION	2.26
5XQX	X-RAY DIFFRACTION	2.3
5HNB	X-RAY DIFFRACTION	2.35
5FGK	X-RAY DIFFRACTION	2.36
5HBE	X-RAY DIFFRACTION	2.38
4F6W	X-RAY DIFFRACTION	2.39
5HVY	X-RAY DIFFRACTION	2.39
4CRL	X-RAY DIFFRACTION	2.4
6T41	X-RAY DIFFRACTION	2.45
6QTJ	X-RAY DIFFRACTION	2.48
5HBH	X-RAY DIFFRACTION	2.5
9H8C	X-RAY DIFFRACTION	2.57
4F6S	X-RAY DIFFRACTION	2.6
4F7J	X-RAY DIFFRACTION	2.6
5I5Z	X-RAY DIFFRACTION	2.6
5BNJ	X-RAY DIFFRACTION	2.64
4F7N	X-RAY DIFFRACTION	2.65
5IDP	X-RAY DIFFRACTION	2.65
4G6L	X-RAY DIFFRACTION	2.7
6QTG	X-RAY DIFFRACTION	2.7
6TPA	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49336-F1	80.75	0.63

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 151 (proton acceptor)

Ligand- & substrate-binding residues (2): 27–35; 52

Mutagenesis-validated functional residues (1):

Position	Phenotype
173	abrogates kinase activity and tfiih-dependent transcriptional repression.

Function

Pathways and Gene Ontology

Reactome pathways

34 pathways

ID	Pathway
R-HSA-1989781	PPARA activates gene expression
R-HSA-2122947	NOTCH1 Intracellular Domain Regulates Transcription
R-HSA-212436	Generic Transcription Pathway
R-HSA-2173796	SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription
R-HSA-2644606	Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2894862	Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-381340	Transcriptional regulation of white adipocyte differentiation
R-HSA-9833110	RSV-host interactions
R-HSA-9841922	MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis
R-HSA-1266738	Developmental Biology
R-HSA-1430728	Metabolism
R-HSA-157118	Signaling by NOTCH
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-170834	Signaling by TGF-beta Receptor Complex
R-HSA-1980143	Signaling by NOTCH1
R-HSA-212165	Epigenetic regulation of gene expression
R-HSA-2173793	Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer
R-HSA-2644602	Signaling by NOTCH1 PEST Domain Mutants in Cancer
R-HSA-2644603	Signaling by NOTCH1 in Cancer
R-HSA-2894858	Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer
R-HSA-400206	Regulation of lipid metabolism by PPARalpha
R-HSA-556833	Metabolism of lipids
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-5663205	Infectious disease
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-9006936	Signaling by TGFB family members
R-HSA-9818564	Epigenetic regulation of gene expression by MLL3 and MLL4 complexes
R-HSA-9820952	Respiratory Syncytial Virus Infection Pathway

MSigDB gene sets: 305 (showing top): REACTOME_TRANSCRIPTIONAL_REGULATION_OF_WHITE_ADIPOCYTE_DIFFERENTIATION, REACTOME_SIGNALING_BY_NOTCH, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, MORF_BRCA1, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, IVANOVA_HEMATOPOIESIS_MATURE_CELL, FRASOR_RESPONSE_TO_SERM_OR_FULVESTRANT_DN, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, SOX9_B1, GOBP_REGULATION_OF_CELL_CYCLE, DACOSTA_UV_RESPONSE_VIA_ERCC3_COMMON_DN, TURASHVILI_BREAST_LOBULAR_CARCINOMA_VS_LOBULAR_NORMAL_DN, GENTILE_UV_HIGH_DOSE_DN, FUJII_YBX1_TARGETS_DN, MAF_Q6

GO Biological Process (3): positive regulation of transcription by RNA polymerase II (GO:0045944), protein phosphorylation (GO:0006468), regulation of cell cycle (GO:0051726)

GO Molecular Function (10): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), cyclin-dependent protein serine/threonine kinase activity (GO:0004693), ATP binding (GO:0005524), RNA polymerase II CTD heptapeptide repeat kinase activity (GO:0008353), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (7): cyclin-dependent protein kinase holoenzyme complex (GO:0000307), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), mediator complex (GO:0016592), protein-containing complex (GO:0032991), CKM complex (GO:1990508)

Reactome top-level categories

Rollup of top-17 pathways:

Category	Pathways
Regulation of lipid metabolism by PPARalpha	1
Signaling by NOTCH1	1
RNA Polymerase II Transcription	1
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1
Adipogenesis	1
Respiratory Syncytial Virus Infection Pathway	1
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1
Signal Transduction	1
Signaling by TGFB family members	1
Signaling by NOTCH	1
Gene expression (Transcription)	1
Signaling by TGF-beta Receptor Complex	1
Generic Transcription Pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein kinase activity	2
protein serine/threonine kinase activity	2
nuclear lumen	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
phosphorylation	1
protein modification process	1
cell cycle	1
regulation of cellular process	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
cyclin-dependent protein kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
RNA polymerase II CTD heptapeptide repeat modifying activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
serine/threonine protein kinase complex	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1
intracellular membraneless organelle	1
core mediator complex	1
nuclear protein-containing complex	1
cellular_component	1
nuclear cyclin-dependent protein kinase holoenzyme complex	1

Protein interactions and networks

STRING

2042 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CDK8	MED12	Q93074	999
CDK8	CCNC	P24863	999
CDK8	MED13	Q9UHV7	997
CDK8	MED6	O75586	948
CDK8	MED12L	Q86YW9	932
CDK8	MED18	Q9BUE0	913
CDK8	CCNH	P51946	900
CDK8	MED13L	Q71F56	897
CDK8	MED17	Q9NVC6	887
CDK8	CCNL2	Q96S94	877
CDK8	MED14	O60244	867
CDK8	MED7	O43513	861
CDK8	MED8	Q96G25	853
CDK8	MED15	Q96RN5	849
CDK8	CDK19	Q9BWU1	838

IntAct

158 interactions, top by confidence:

A	B	Type	Score
CCNC	CDK8	psi-mi:“MI:0915”(physical association)	0.980
CDK8	CCNC	psi-mi:“MI:0915”(physical association)	0.980
CDK8	CCNC	psi-mi:“MI:0407”(direct interaction)	0.980
CCNC	CDK8	psi-mi:“MI:0407”(direct interaction)	0.980
CCNC	CDK8	psi-mi:“MI:0914”(association)	0.980
CCNC	CDK8	psi-mi:“MI:2364”(proximity)	0.980
CCNC	CDK8	psi-mi:“MI:0217”(phosphorylation reaction)	0.980
CDK8	CCNC	psi-mi:“MI:0914”(association)	0.980
CDK8	MED1	psi-mi:“MI:0914”(association)	0.920

BioGRID (627): CDK8 (Two-hybrid), CDK8 (Affinity Capture-MS), CDK8 (Affinity Capture-MS), CDK8 (Affinity Capture-MS), MED6 (Affinity Capture-MS), MED4 (Affinity Capture-MS), MED28 (Affinity Capture-MS), MED17 (Affinity Capture-MS), MED23 (Affinity Capture-MS), MED29 (Affinity Capture-MS), MED22 (Affinity Capture-MS), MED24 (Affinity Capture-MS), MED10 (Affinity Capture-MS), CDK16 (Affinity Capture-MS), MED15 (Affinity Capture-MS)

ESM2 similar proteins: A2VEA3, A5PKA5, A7MB76, O70133, O89050, P09851, P17427, P18484, P20595, P20936, P49336, P50904, P79101, P97834, Q08211, Q12800, Q28141, Q2MHE5, Q2TBL9, Q32NS4, Q3MHJ2, Q3UHD6, Q5M887, Q5R4Q7, Q5R874, Q5RB35, Q5RBN9, Q5RCG0, Q6GR10, Q6P5H6, Q6PKX4, Q7SXR3, Q7T2U9, Q7Z6J6, Q86TJ2, Q8K4V4, Q8N653, Q8R3L8, Q8R3S6, Q96DM3

Diamond homologs: A1CL96, A1D624, A2QU77, A2X6X1, A2XUW1, A3LUB9, A4QXX4, A8XA58, O13958, O55076, O61847, O96821, P00546, P06493, P0C661, P0CS76, P0CS77, P11440, P21127, P23111, P23437, P23572, P24033, P24100, P24788, P24923, P24941, P29618, P29619, P34112, P34117, P34556, P35567, P39073, P39951, P43063, P43450, P46892, P48734, P48963

SIGNOR signaling

34 interactions.

A	Effect	B	Mechanism
CDK8	“up-regulates quantity by expression”	HES1	“transcriptional regulation”
CDK8	down-regulates	NOTCH1	phosphorylation
MAML1	up-regulates	CDK8	binding
MAML1	up-regulates	CDK8	relocalization
CDK8	“down-regulates activity”	SMAD3	phosphorylation
CDK8	down-regulates	SMAD3	phosphorylation
CDK8	down-regulates	SMAD1	phosphorylation
CDK8	down-regulates	E2F1	phosphorylation
CDK8	“down-regulates quantity by destabilization”	SMAD1	phosphorylation
CDK8	down-regulates	NOTCH	phosphorylation
CDK8	“form complex”	“CKM complex”	binding
CDK8	down-regulates	CDKN1B	phosphorylation
CDK8	“down-regulates quantity by destabilization”	MED13	phosphorylation
CDK8	“up-regulates activity”	SREBF1	phosphorylation
CDK8	down-regulates	CCNH	phosphorylation
CDK8	“down-regulates activity”	H3C1	phosphorylation
CDK8	“down-regulates activity”	H3-3A	phosphorylation
CDK8	“down-regulates activity”	H3-4	phosphorylation
CDK8	“down-regulates quantity by destabilization”	NOTCH1	phosphorylation
CDK8	“up-regulates activity”	STAT1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 70 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Respiratory Syncytial Virus Infection Pathway	25	82.0×	1e-41
Adipogenesis	27	70.4×	9e-43
RSV-host interactions	25	65.2×	6e-39
Regulation of lipid metabolism by PPARalpha	26	61.1×	1e-39
Transcriptional regulation of white adipocyte differentiation	27	58.4×	1e-40
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	15	53.9×	3e-21
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	15	49.2×	1e-20
PPARA activates gene expression	27	42.5×	1e-36

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of transcription elongation by RNA polymerase II	24	111.1×	2e-42
positive regulation of transcription initiation by RNA polymerase II	24	100.4×	3e-41
RNA polymerase II preinitiation complex assembly	23	96.2×	4e-39
transcription initiation at RNA polymerase II promoter	8	46.1×	8e-10
somatic stem cell population maintenance	11	41.9×	2e-13
positive regulation of miRNA transcription	6	26.8×	7e-06
transcription by RNA polymerase II	9	9.8×	2e-05
protein ubiquitination	10	6.4×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

115 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	9
Uncertain significance	66
Likely benign	10
Benign	2

Top pathogenic / likely-pathogenic (19)

Variant ID	HGVS	Classification
3358926	NM_001260.3(CDK8):c.533G>A (p.Arg178Gln)	Pathogenic
3368754	NM_001260.3(CDK8):c.79G>C (p.Val27Leu)	Pathogenic
3767612	NM_001260.3(CDK8):c.467A>G (p.Asn156Ser)	Pathogenic
631491	NM_001260.3(CDK8):c.185C>A (p.Ser62Ter)	Pathogenic
805981	NM_001260.3(CDK8):c.185C>T (p.Ser62Leu)	Pathogenic
805982	NM_001260.3(CDK8):c.85C>G (p.Arg29Gly)	Pathogenic
805983	NM_001260.3(CDK8):c.88G>A (p.Gly30Ser)	Pathogenic
805984	NM_001260.3(CDK8):c.578T>G (p.Val193Gly)	Pathogenic
805985	NM_001260.3(CDK8):c.669A>G (p.Ile223Met)	Pathogenic
871513	NM_001260.3(CDK8):c.88G>T (p.Gly30Cys)	Pathogenic
1802178	NM_001260.3(CDK8):c.89G>T (p.Gly30Val)	Likely pathogenic
1810411	NM_001260.3(CDK8):c.586A>T (p.Thr196Ser)	Likely pathogenic
3236205	NM_001260.3(CDK8):c.185C>G (p.Ser62Trp)	Likely pathogenic
3371496	NM_001260.3(CDK8):c.584T>C (p.Val195Ala)	Likely pathogenic
4057251	NM_001260.3(CDK8):c.563C>G (p.Ala188Gly)	Likely pathogenic
4531450	NM_001260.3(CDK8):c.101A>C (p.His34Pro)	Likely pathogenic
4538915	NM_001260.3(CDK8):c.521T>C (p.Met174Thr)	Likely pathogenic
982990	NM_001260.3(CDK8):c.479T>C (p.Met160Thr)	Likely pathogenic
996136	NM_001260.3(CDK8):c.587C>T (p.Thr196Ile)	Likely pathogenic

SpliceAI

2622 predictions. Top by Δscore:

Variant	Effect	Δscore
13:26254762:A:T	donor_gain	1.0000
13:26337638:TAGCA:T	donor_gain	1.0000
13:26337639:AGCA:A	donor_gain	1.0000
13:26337640:GCA:G	donor_gain	1.0000
13:26337640:GCAG:G	donor_gain	1.0000
13:26337641:CA:C	donor_gain	1.0000
13:26337643:G:GG	donor_gain	1.0000
13:26349070:A:AG	acceptor_gain	1.0000
13:26349071:G:GG	acceptor_gain	1.0000
13:26353738:A:AG	acceptor_gain	1.0000
13:26353739:G:GG	acceptor_gain	1.0000
13:26353739:GC:G	acceptor_gain	1.0000
13:26353739:GCAT:G	acceptor_gain	1.0000
13:26353739:GCATA:G	acceptor_gain	1.0000
13:26353878:TTGGT:T	donor_loss	1.0000
13:26353879:TGGTA:T	donor_loss	1.0000
13:26353880:GGTA:G	donor_loss	1.0000
13:26353881:G:A	donor_loss	1.0000
13:26353881:G:GG	donor_gain	1.0000
13:26353882:TAAGT:T	donor_loss	1.0000
13:26353883:AAGTT:A	donor_loss	1.0000
13:26385200:T:G	acceptor_gain	1.0000
13:26385207:ACAGC:A	acceptor_loss	1.0000
13:26385208:C:G	acceptor_gain	1.0000
13:26385209:A:AG	acceptor_gain	1.0000
13:26385209:A:G	acceptor_loss	1.0000
13:26385209:AGCT:A	acceptor_gain	1.0000
13:26385210:G:GA	acceptor_gain	1.0000
13:26385210:GC:G	acceptor_gain	1.0000
13:26385210:GCT:G	acceptor_gain	1.0000

AlphaMissense

3059 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:26254699:T:C	F20L	1.000
13:26254700:T:C	F20S	1.000
13:26254701:T:A	F20L	1.000
13:26254701:T:G	F20L	1.000
13:26254719:A:C	K26N	1.000
13:26254719:A:T	K26N	1.000
13:26254721:T:A	V27D	1.000
13:26254723:G:C	G28R	1.000
13:26254723:G:T	G28C	1.000
13:26254724:G:A	G28D	1.000
13:26254724:G:T	G28V	1.000
13:26254727:G:C	R29P	1.000
13:26254729:G:A	G30S	1.000
13:26254729:G:C	G30R	1.000
13:26254729:G:T	G30C	1.000
13:26254730:G:A	G30D	1.000
13:26254730:G:C	G30A	1.000
13:26254730:G:T	G30V	1.000
13:26254733:C:T	T31I	1.000
13:26254735:T:A	Y32N	1.000
13:26254735:T:C	Y32H	1.000
13:26254735:T:G	Y32D	1.000
13:26254736:A:G	Y32C	1.000
13:26254738:G:A	G33S	1.000
13:26254738:G:C	G33R	1.000
13:26254738:G:T	G33C	1.000
13:26254739:G:A	G33D	1.000
13:26254739:G:T	G33V	1.000
13:26254744:G:C	V35L	1.000
13:26254744:G:T	V35F	1.000

dbSNP variants (sampled 300 via entrez): RS1000009077 (13:26269693 T>C), RS1000029689 (13:26363576 G>A), RS1000030007 (13:26279317 C>T), RS1000035621 (13:26271481 T>C), RS1000099517 (13:26271014 G>A,T), RS1000101662 (13:26279583 C>G,T), RS1000127542 (13:26253920 G>T), RS1000155087 (13:26319429 A>G), RS1000196289 (13:26392366 C>T), RS1000212131 (13:26296150 T>C), RS1000221038 (13:26339530 A>C), RS1000234392 (13:26383274 G>A), RS1000270267 (13:26294579 G>T), RS1000296821 (13:26332229 A>G), RS1000302542 (13:26309406 T>G)

Disease associations

OMIM: gene MIM:603184 | disease phenotypes: MIM:618748, MIM:618321, MIM:142340, MIM:224700

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual developmental disorder with hypotonia and behavioral abnormalities	Definitive	Autosomal dominant

Mondo (6): intellectual developmental disorder with hypotonia and behavioral abnormalities (MONDO:0032897), intellectual disability (MONDO:0001071), NAD(P)HX dehydratase deficiency (MONDO:0034121), congenital diaphragmatic hernia (MONDO:0005711), Ebstein anomaly (MONDO:0009144), complex neurodevelopmental disorder with or without congenital anomalies (MONDO:0100465)

Orphanet (4): NAD(P)HX dehydratase deficiency (Orphanet:555402), Ebstein malformation of the tricuspid valve (Orphanet:1880), Congenital diaphragmatic hernia (Orphanet:2140), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000545	Myopia
HP:0000729	Autistic behavior
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001270	Motor delay
HP:0001274	Agenesis of corpus callosum
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001545	Anteriorly placed anus
HP:0001629	Ventricular septal defect
HP:0001636	Tetralogy of Fallot
HP:0001655	Patent foramen ovale
HP:0001680	Coarctation of aorta
HP:0001999	Abnormal facial shape
HP:0002572	Episodic vomiting
HP:0004383	Hypoplastic left ventricle
HP:0004792	Rectoperineal fistula
HP:0007018	Attention deficit hyperactivity disorder
HP:0008872	Feeding difficulties in infancy
HP:0011330	Metopic synostosis

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002441_1	Immune response to measles-mumps-rubella vaccine	3.000000e-07
GCST002940_4	Sporadic pituitary adenoma	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004645	response to vaccine

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D004437	Ebstein Anomaly	C14.240.400.395; C14.280.400.395; C16.131.240.400.395
D065630	Hernias, Diaphragmatic, Congenital	C16.131.433; C23.300.707.960.500.116
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (6): CHEMBL3038474 (PROTEIN COMPLEX), CHEMBL3559691 (PROTEIN FAMILY), CHEMBL3885556 (PROTEIN FAMILY), CHEMBL4296125 (PROTEIN-PROTEIN INTERACTION), CHEMBL5719 (SINGLE PROTEIN), CHEMBL6066143 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

23 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 168,903 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL1171837	PONATINIB	4	8,955
CHEMBL576982	QUIZARTINIB	4	4,432
CHEMBL101253	VATALANIB	3	11,319
CHEMBL2103840	DINACICLIB	3	2,257
CHEMBL223360	LINIFANIB	3	3,925
CHEMBL38380	FASUDIL	3	11,953
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL483158	ALISERTIB	3	2,305
CHEMBL603469	LESTAURTINIB	3
CHEMBL1276127	INDIRUBIN	2	181
CHEMBL103667	DORAMAPIMOD	2	1,681
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL1980297	ILORASERTIB	2	581
CHEMBL3905910	VORUCICLIB	2	856
CHEMBL4297488	CT-7001	2	379
CHEMBL483321	CP-724714	2	872
CHEMBL4076837	SENEXIN B	1	104
CHEMBL4225966	SEL-120 FREE BASE	1	91
CHEMBL296468	BMS-387032	1	2,075
CHEMBL4578881	SEL-120	1
CHEMBL482767	SNS-314	1
CHEMBL574738	AST-487	1

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — CDK8 subfamily

Most potent curated ligand interactions (13 total), top 13:

Ligand	Action	Affinity	Parameter
CCT251545	Inhibition	8.42	pKd
romaciclib	Inhibition	8.36	pIC50
compound 51 [Mallinger et al., 2016]	Inhibition	8.29	pIC50
ponatinib	Inhibition	8.17	pKd
linifanib	Inhibition	8.16	pKd
voruciclib	Inhibition	7.92	pIC50
JH-VIII-49	Inhibition	7.8	pIC50
cortistatin A	Inhibition	7.77	pKd
compound 20 [Bergeron et al., 2016]	Inhibition	7.76	pIC50
DS96432529	Inhibition	7.48	pIC50
sorafenib	Inhibition	7.0	pKd
JH-XI-10-02	Inhibition	6.8	pIC50
CDK12 inhibitor 2	Inhibition	5.0	pIC50

Binding affinities (BindingDB)

121 measured of 125 human assays (125 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
1-[2-(4-methylphenyl)-5-tert-butyl-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	KD	0.37 nM
5-cyclopropyl-7,7-dimethyl-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-4-carboxamide	IC50	0.48 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
3-ethylspiro[8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-7,1’-cyclohexane]-4-carboxamide	IC50	0.77 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
3-(2-fluoroethyl)spiro[8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-7,1’-cyclobutane]-4-carboxamide	IC50	0.827 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
3-ethyl-7,7-dimethyl-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-4-carboxamide	IC50	1.09 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
spiro[8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-7,1’-cyclobutane]-4-carboxamide	IC50	1.41 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
3,7,7-trimethyl-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-4-carboxamide	IC50	1.41 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
13-chloro-7,7-dimethyl-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(13),2(6),4,9,11-pentaene-4-carboxamide	IC50	1.41 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
3-(2-fluoroethyl)-7,7-dimethyl-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-4-carboxamide	IC50	1.41 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
7-cyclohexyl-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-4-carboxamide	IC50	1.41 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
3-ethylspiro[8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-7,1’-cyclobutane]-4-carboxamide	IC50	1.41 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
3-methylspiro[8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-7,1’-cyclobutane]-4-carboxamide	IC50	1.41 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
3-methylspiro[8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-7,1’-cyclohexane]-4-carboxamide	IC50	1.41 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
(7S)-7-cyclohexyl-3-ethyl-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-4-carboxamide	IC50	1.41 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
(7R)-7-cyclohexyl-3-ethyl-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-4-carboxamide	IC50	1.41 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
Staurosporine	KD	1.7 nM
5-chloro-3-ethylspiro[8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-7,4’-oxane]-4-carboxamide	IC50	2.41 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
5-cyclopropyl-3-ethyl-7,7-dimethyl-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-4-carboxamide	IC50	2.65 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
spiro[8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-7,1’-cyclohexane]-4-carboxylic acid	IC50	3.01 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
3-ethyl-1’-(2,2,2-trifluoroethyl)spiro[8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-7,4’-piperidine]-4-carboxamide	IC50	3.14 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
4-[2-[6-[4-(3-hydroxypropyl)piperazine-1-carbonyl]naphthalen-2-yl]ethylamino]quinoline-6-carbonitrile	IC50	4.1 nM	US-12281080: Quinoline-based compounds and methods of inhibiting CDK8/19
(7S)-7-(oxan-4-yl)-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-4-carboxamide	IC50	4.46 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
3-ethylspiro[8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-7,4’-oxane]-4-carboxamide	IC50	4.58 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
4-[2-[6-(1-oxo-1,4-thiazinane-4-carbonyl)naphthalen-2-yl]ethylamino]quinoline-6-carbonitrile	IC50	5.8 nM	US-12281080: Quinoline-based compounds and methods of inhibiting CDK8/19
3-methylspiro[8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-7,4’-oxane]-4-carboxamide	IC50	6.1 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
1’-acetylspiro[8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-7,4’-piperidine]-4-carboxamide	IC50	7.48 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
spiro[8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-7,1’-cyclohexane]-4-carboxamide	IC50	8.22 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
(7S)-7-cyclohexyl-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-4-carboxamide	IC50	8.5 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
3-(2-methoxyethyl)-7,7-dimethyl-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-4-carboxamide	IC50	11.5 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
7,7-dimethyl-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-4-carboxamide	IC50	11.9 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
3-ethyl-5-(3-methoxyphenyl)-7,7-dimethyl-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-4-carboxamide	IC50	13.9 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
7-methyl-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-4-carboxamide	IC50	14.4 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
3-ethyl-5-(2-methoxyphenyl)-7,7-dimethyl-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-4-carboxamide	IC50	16.4 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
5-chloro-7,7-dimethyl-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-4-carboxamide	IC50	16.6 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
3-ethyl-7,7-dimethyl-5-[2-(trifluoromethyl)phenyl]-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-4-carboxamide	IC50	16.7 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
(7R)-7-cyclohexyl-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-4-carboxamide	IC50	19.3 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
7,7-dimethyl-3-(2,2,2-trifluoroethyl)-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-4-carboxamide	IC50	19.4 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
7,7-dimethyl-5-(4-sulfamoylphenyl)-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-4-carboxylic acid	IC50	20.7 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
3-(2-methoxyethyl)spiro[8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-7,4’-oxane]-4-carboxamide	IC50	20.9 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
5-ethenyl-7,7-dimethyl-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-4-carboxamide	IC50	29.5 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
7-methyl-7-propan-2-yl-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-4-carboxamide	IC50	31.1 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
13-chloro-7,7-dimethyl-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(13),2(6),4,9,11-pentaene-4-carboxylic acid	IC50	31.4 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
1’-(2,2,2-trifluoroethyl)spiro[8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-7,4’-piperidine]-4-carboxamide	IC50	40.5 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
5-(3,6-dihydro-2H-pyran-4-yl)-7,7-dimethyl-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-4-carboxamide	IC50	70.5 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
7,7-dimethyl-5-(4-sulfamoylphenyl)-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-4-carboxamide	IC50	81.3 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
5-(3,6-dihydro-2H-pyran-4-yl)-7,7-dimethyl-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-4-carboxylic acid	IC50	86.6 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
3-(2-fluoroethyl)-5-(2-methoxyphenyl)-7,7-dimethyl-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-4-carboxamide	IC50	97.3 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
7,7-dimethyl-5-phenyl-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-4-carboxamide	IC50	107 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
5-(2-hydroxyphenyl)-7,7-dimethyl-8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-4-carboxamide	IC50	112 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors
1’-(3,3,3-trifluoropropyl)spiro[8-oxa-3,11-diazatricyclo[7.4.0.02,6]trideca-1(9),2(6),4,10,12-pentaene-7,4’-piperidine]-4-carboxamide	IC50	120 nM	US-10208056: Condensed tricyclic compounds as protein kinase inhibitors

ChEMBL bioactivities

1516 potent at pChembl≥5 of 1554 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.10	IC50	0.08	nM	CHEMBL3799396
9.72	IC50	0.191	nM	CHEMBL4789125
9.70	IC50	0.2	nM	CHEMBL3827983
9.70	IC50	0.2	nM	CHEMBL4078454
9.58	IC50	0.262	nM	CHEMBL4789603
9.56	IC50	0.278	nM	CHEMBL4776812
9.50	IC50	0.314	nM	CHEMBL4777356
9.47	IC50	0.34	nM	CHEMBL4083552
9.46	EC50	0.35	nM	CHEMBL4071040
9.43	IC50	0.37	nM	CHEMBL5435821
9.40	IC50	0.4	nM	CHEMBL4096487
9.40	EC50	0.4	nM	CHEMBL4086487
9.40	IC50	0.4	nM	CHEMBL5434183
9.40	IC50	0.4	nM	CHEMBL5409410
9.39	IC50	0.407	nM	CHEMBL5752178
9.34	IC50	0.46	nM	CHEMBL4066819
9.33	IC50	0.47	nM	CHEMBL4070408
9.33	IC50	0.466	nM	CHEMBL4780792
9.32	IC50	0.48	nM	CHEMBL5405004
9.31	IC50	0.49	nM	CHEMBL5414359
9.30	IC50	0.5	nM	CHEMBL3828116
9.27	IC50	0.54	nM	CHEMBL4091527
9.24	EC50	0.58	nM	CHEMBL4061525
9.24	IC50	0.57	nM	CHEMBL4086487
9.23	IC50	0.59	nM	CHEMBL4061525
9.22	IC50	0.6	nM	CHEMBL3798726
9.22	IC50	0.6	nM	CHEMBL3828003
9.22	IC50	0.6	nM	CHEMBL3956719
9.22	IC50	0.6	nM	CHEMBL4074204
9.20	IC50	0.63	nM	CHEMBL5416117
9.19	IC50	0.65	nM	CHEMBL4082469
9.15	IC50	0.7	nM	CHEMBL3798611
9.15	IC50	0.7	nM	CHEMBL498385
9.15	IC50	0.71	nM	CHEMBL3828221
9.15	IC50	0.71	nM	CHEMBL5402477
9.15	IC50	0.7	nM	CHEMBL5396725
9.11	EC50	0.77	nM	CHEMBL4083552
9.11	Kd	0.77	nM	CHEMBL4455382
9.10	Kd	0.7943	nM	CHEMBL6163999
9.10	Ki	0.7943	nM	CHEMBL1986943
9.08	IC50	0.83	nM	CHEMBL5411825
9.06	IC50	0.88	nM	CHEMBL5440319
9.05	IC50	0.9	nM	CHEMBL3828637
9.05	IC50	0.9	nM	CHEMBL5416758
9.03	IC50	0.93	nM	CHEMBL4060856
9.00	IC50	1	nM	CHEMBL3797571
9.00	IC50	1	nM	CHEMBL3806220
9.00	IC50	1	nM	CHEMBL3828458
9.00	IC50	0.99	nM	CHEMBL4062244
9.00	IC50	1	nM	CHEMBL4455382

PubChem BioAssay actives

1054 with measured affinity, of 2583 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
8-[3-chloro-5-(1-methyl-2,2-dioxo-3H-2,1-benzothiazol-5-yl)-4-pyridinyl]-1-methyl-2,3,8-triazaspiro[4.5]dec-1-en-4-one	1295749: Binding affinity to CDK8/CDK19 in human 7dF3 cells preincubated for 2 hrs followed by addition 10 uM of beta-oestradiol measured after 24 hrs by luciferase reporter gene assay	ic50	0.0001	uM
N-methyl-8-[4-(1-methylpyrazol-4-yl)phenyl]-1,6-naphthyridine-2-carboxamide	1313397: Binding affinity to CDK8 (unknown origin) expressed in human 7dF3 cells preincubated for 2 hrs followed by beta-oestradiol addition measured after 24 hrs by luciferase reporter gene assay	ic50	0.0002	uM
2-chloro-4-[6-[[(1R)-2-hydroxy-1-phenylethyl]amino]pyrazin-2-yl]phenol	1474371: Inhibition of full length recombinant human His-tagged CDK8/Cyclin C expressed in baculovirus expression system using Ulight-GS peptide as substrate measured after 30 mins by TR-FRET based LANCE assay	ic50	0.0002	uM
8-phenoxy-4,5-dihydrothieno[3,4-g][1,2]benzothiazole-6-carboxamide	1474368: Inhibition of kinase tracer-236 binding to GST-tagged CDK8/CyclinC (unknown origin) after 60 mins by TR-FRET assay	ic50	0.0003	uM
8-[[6-(2-methoxyethylcarbamoyl)-2-methyl-3-pyridinyl]oxy]-4,5-dihydrothieno[3,4-g][1,2]benzothiazole-6-carboxamide	1474306: Inhibition of CDK8 in human SW620 cells assessed as decrease in STAT1 phosphorylation at Ser727 after 2 hrs by Western blot method	ec50	0.0003	uM
8-[(6-acetamido-3-pyridinyl)oxy]-4,5-dihydrothieno[3,4-g][1,2]benzothiazole-6-carboxamide	1474306: Inhibition of CDK8 in human SW620 cells assessed as decrease in STAT1 phosphorylation at Ser727 after 2 hrs by Western blot method	ec50	0.0004	uM
5-[(5S)-5-(4-chlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]-3-methyl-2H-indazole	2030640: Inhibition of His tagged human recombinant CDK8/Cyclin C expressed in baculovirus expression system incubated for 15 mins by FRET-based LanthaScreen binding competition assay	ic50	0.0004	uM
5-[5-[(4-chlorophenyl)methyl]-1-methyltriazol-4-yl]-3-methyl-2H-indazole	2030640: Inhibition of His tagged human recombinant CDK8/Cyclin C expressed in baculovirus expression system incubated for 15 mins by FRET-based LanthaScreen binding competition assay	ic50	0.0004	uM
(5S)-5-(4-chlorophenyl)-3-(3-methyl-2H-indazol-5-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine	2030640: Inhibition of His tagged human recombinant CDK8/Cyclin C expressed in baculovirus expression system incubated for 15 mins by FRET-based LanthaScreen binding competition assay	ic50	0.0004	uM
(2R)-2-[[5-(1H-indazol-5-yl)-3-pyridinyl]amino]-2-phenylethanol	1474371: Inhibition of full length recombinant human His-tagged CDK8/Cyclin C expressed in baculovirus expression system using Ulight-GS peptide as substrate measured after 30 mins by TR-FRET based LANCE assay	ic50	0.0004	uM
8-[4-(1-methylpyrazol-4-yl)phenyl]-1,6-naphthyridine-2-carboxamide	1313397: Binding affinity to CDK8 (unknown origin) expressed in human 7dF3 cells preincubated for 2 hrs followed by beta-oestradiol addition measured after 24 hrs by luciferase reporter gene assay	ic50	0.0005	uM
8-[[6-(2-methoxyethylcarbamoyl)-3-pyridinyl]oxy]-4,5-dihydrothieno[3,4-g][1,2]benzothiazole-6-carboxamide	1474368: Inhibition of kinase tracer-236 binding to GST-tagged CDK8/CyclinC (unknown origin) after 60 mins by TR-FRET assay	ic50	0.0005	uM
8-[(2-methyl-3-pyridinyl)oxy]-4,5-dihydrothieno[3,4-g][1,2]benzothiazole-6-carboxamide	1474368: Inhibition of kinase tracer-236 binding to GST-tagged CDK8/CyclinC (unknown origin) after 60 mins by TR-FRET assay	ic50	0.0005	uM
(E)-N-[4-(morpholin-4-ylmethyl)phenyl]-3-[4-(1H-pyrazol-4-yl)-3-pyridinyl]prop-2-enamide	1466029: Inhibition of kinase tracer 236 binding to full length N terminal GST-tagged human CDK8 (1 to 464 end residues) /CycC ( 1 to 283 end residues) expressed in baculovirus expression system after 60 min by TR-FRET assay	ic50	0.0005	uM
5-[4-[(4-chlorophenyl)methyl]-5-methyl-1,2,4-triazol-3-yl]-3-methyl-2H-indazole	2030640: Inhibition of His tagged human recombinant CDK8/Cyclin C expressed in baculovirus expression system incubated for 15 mins by FRET-based LanthaScreen binding competition assay	ic50	0.0005	uM
(5R)-5-(4-chlorophenyl)-3-(3-methyl-2H-indazol-5-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine	2030640: Inhibition of His tagged human recombinant CDK8/Cyclin C expressed in baculovirus expression system incubated for 15 mins by FRET-based LanthaScreen binding competition assay	ic50	0.0005	uM
N-methyl-4-[4-(1-methylpyrazol-4-yl)phenyl]isoquinoline-6-carboxamide	1313397: Binding affinity to CDK8 (unknown origin) expressed in human 7dF3 cells preincubated for 2 hrs followed by beta-oestradiol addition measured after 24 hrs by luciferase reporter gene assay	ic50	0.0006	uM
8-methylsulfanyl-4,5-dihydrothieno[3,4-g][1,2]benzothiazole-6-carboxamide	1474368: Inhibition of kinase tracer-236 binding to GST-tagged CDK8/CyclinC (unknown origin) after 60 mins by TR-FRET assay	ic50	0.0006	uM
8-[(6-amino-3-pyridinyl)oxy]-4,5-dihydrothieno[3,4-g][1,2]benzothiazole-6-carboxamide	1474368: Inhibition of kinase tracer-236 binding to GST-tagged CDK8/CyclinC (unknown origin) after 60 mins by TR-FRET assay	ic50	0.0006	uM
8-[[6-(methylamino)-3-pyridinyl]oxy]-4,5-dihydrothieno[3,4-g][1,2]benzothiazole-6-carboxamide	1474306: Inhibition of CDK8 in human SW620 cells assessed as decrease in STAT1 phosphorylation at Ser727 after 2 hrs by Western blot method	ec50	0.0006	uM
8-[3-(1-methyl-2,2-dioxo-3H-2,1-benzothiazol-5-yl)-5-(trifluoromethyl)-4-pyridinyl]-2,8-diazaspiro[4.5]decan-1-one	1295749: Binding affinity to CDK8/CDK19 in human 7dF3 cells preincubated for 2 hrs followed by addition 10 uM of beta-oestradiol measured after 24 hrs by luciferase reporter gene assay	ic50	0.0006	uM
(5R)-5-(4-chlorophenyl)-3-(3-methyl-2H-indazol-5-yl)-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazine	2030640: Inhibition of His tagged human recombinant CDK8/Cyclin C expressed in baculovirus expression system incubated for 15 mins by FRET-based LanthaScreen binding competition assay	ic50	0.0006	uM
[(2S)-2-(4-chlorophenyl)pyrrolidin-1-yl]-(3-methyl-2H-indazol-5-yl)methanone	1315917: Inhibition of CDK8 in human 7dF3 cells preincubated for 2 hrs followed by beta-oestradiol addition measured after 24 hrs by luciferase reporter gene assay	ic50	0.0006	uM
8-[3-chloro-5-[4-(1-methylpyrazol-4-yl)phenyl]-4-pyridinyl]-1-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione	1295749: Binding affinity to CDK8/CDK19 in human 7dF3 cells preincubated for 2 hrs followed by addition 10 uM of beta-oestradiol measured after 24 hrs by luciferase reporter gene assay	ic50	0.0007	uM
2-(1-methylimidazol-2-yl)-8-[4-(1-methylpyrazol-4-yl)phenyl]-1,6-naphthyridine	1313396: Competitive binding affinity to full length His-tagged human recombinant CDK8/cyclin C expressed in baculovirus after 20 mins in presence of Alexa647 tracer by FRET assay	ic50	0.0007	uM
3-methyl-5-[5-methyl-4-[[4-(trifluoromethyl)phenyl]methyl]-1,2,4-triazol-3-yl]-2H-indazole	2030640: Inhibition of His tagged human recombinant CDK8/Cyclin C expressed in baculovirus expression system incubated for 15 mins by FRET-based LanthaScreen binding competition assay	ic50	0.0007	uM
5-[5-[(4-chlorophenyl)methyl]-1-methylpyrazol-4-yl]-3-methyl-2H-indazole	2030640: Inhibition of His tagged human recombinant CDK8/Cyclin C expressed in baculovirus expression system incubated for 15 mins by FRET-based LanthaScreen binding competition assay	ic50	0.0007	uM
4-(4-iodophenoxy)-2-(2H-tetrazol-5-yl)thieno[2,3-c]pyridine	1299821: Inhibition of full length human recombinant His-tagged CDK8/Cyclin C expressed in baculovirus expression system by fluorescence polarization assay	ic50	0.0007	uM
2-[4-(4-isoquinolin-4-ylphenyl)pyrazol-1-yl]-N,N-dimethylacetamide	1541945: Binding affinity to CDK8 (unknown origin)	kd	0.0008	uM
(5R)-5-(4-chlorophenyl)-7-methyl-3-(3-methyl-2H-indazol-5-yl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine	2030640: Inhibition of His tagged human recombinant CDK8/Cyclin C expressed in baculovirus expression system incubated for 15 mins by FRET-based LanthaScreen binding competition assay	ic50	0.0008	uM
N-methyl-8-(1-methyl-2,2-dioxo-3H-2,1-benzothiazol-5-yl)-1,6-naphthyridine-2-carboxamide	1313396: Competitive binding affinity to full length His-tagged human recombinant CDK8/cyclin C expressed in baculovirus after 20 mins in presence of Alexa647 tracer by FRET assay	ic50	0.0009	uM
8-[(6-carbamoyl-3-pyridinyl)oxy]-4,5-dihydrothieno[3,4-g][1,2]benzothiazole-6-carboxamide	1474368: Inhibition of kinase tracer-236 binding to GST-tagged CDK8/CyclinC (unknown origin) after 60 mins by TR-FRET assay	ic50	0.0009	uM
5-[(5S)-5-(4-chlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]-3-methyl-2H-pyrazolo[4,3-b]pyridine	2030640: Inhibition of His tagged human recombinant CDK8/Cyclin C expressed in baculovirus expression system incubated for 15 mins by FRET-based LanthaScreen binding competition assay	ic50	0.0009	uM
3-chloro-5-[4-[(4-chlorophenyl)methyl]-5-methyl-1,2,4-triazol-3-yl]-2H-indazole	2030640: Inhibition of His tagged human recombinant CDK8/Cyclin C expressed in baculovirus expression system incubated for 15 mins by FRET-based LanthaScreen binding competition assay	ic50	0.0009	uM
1-[8-[4-(1-methylpyrazol-4-yl)phenyl]-1,6-naphthyridin-2-yl]imidazolidin-2-one	1313396: Competitive binding affinity to full length His-tagged human recombinant CDK8/cyclin C expressed in baculovirus after 20 mins in presence of Alexa647 tracer by FRET assay	ic50	0.0010	uM
8-[(6-methyl-3-pyridinyl)oxy]-4,5-dihydrothieno[3,4-g][1,2]benzothiazole-6-carboxamide	1474368: Inhibition of kinase tracer-236 binding to GST-tagged CDK8/CyclinC (unknown origin) after 60 mins by TR-FRET assay	ic50	0.0010	uM
8-[3-chloro-5-(1-methyl-2,2-dioxo-3H-2,1-benzothiazol-5-yl)-4-pyridinyl]-2,8-diazaspiro[4.5]decan-1-one	1295749: Binding affinity to CDK8/CDK19 in human 7dF3 cells preincubated for 2 hrs followed by addition 10 uM of beta-oestradiol measured after 24 hrs by luciferase reporter gene assay	ic50	0.0010	uM
4-[2-(2H-tetrazol-5-yl)thieno[2,3-c]pyridin-4-yl]oxybenzonitrile	1299821: Inhibition of full length human recombinant His-tagged CDK8/Cyclin C expressed in baculovirus expression system by fluorescence polarization assay	ic50	0.0010	uM
8-[3-chloro-5-(1-methylindazol-5-yl)-2H-pyrazolo[3,4-b]pyridin-4-yl]-2,8-diazaspiro[4.5]decan-1-one	1769449: Inhibition of tracer 236 binding to recombinant human His-tagged full length CDK8/Cyclin C expressed in baculovirus expression system by Lanthascreen assay	ic50	0.0010	uM
4-(4-methylpiperazin-1-yl)-N-[4-(2-methyl-3-propan-2-ylindazol-5-yl)pyrimidin-2-yl]quinolin-7-amine	1771106: Inhibition of human CDK8/cyclin C incubated for 2 hrs by [gamma-33P]-ATP assay	ic50	0.0010	uM
4-(4-methylpiperazin-1-yl)-N-[4-(2-methyl-3-propan-2-ylindazol-5-yl)pyrimidin-2-yl]quinazolin-7-amine	2103769: Inhibition of CDK8 (unknown origin)	ic50	0.0010	uM
N-cyclopropyl-4-[4-(1-methylpyrazol-4-yl)phenyl]isoquinoline-6-carboxamide	1313397: Binding affinity to CDK8 (unknown origin) expressed in human 7dF3 cells preincubated for 2 hrs followed by beta-oestradiol addition measured after 24 hrs by luciferase reporter gene assay	ic50	0.0011	uM
[5-amino-8-[4-(1-methylpyrazol-4-yl)phenyl]-1,6-naphthyridin-2-yl]-(3-methoxyazetidin-1-yl)methanone	1313396: Competitive binding affinity to full length His-tagged human recombinant CDK8/cyclin C expressed in baculovirus after 20 mins in presence of Alexa647 tracer by FRET assay	ic50	0.0011	uM
8-[[6-(2-ethoxyethylcarbamoyl)-3-pyridinyl]oxy]-4,5-dihydrothieno[3,4-g][1,2]benzothiazole-6-carboxamide	1474368: Inhibition of kinase tracer-236 binding to GST-tagged CDK8/CyclinC (unknown origin) after 60 mins by TR-FRET assay	ic50	0.0011	uM
2-(2H-tetrazol-5-yl)-4-[4-(trifluoromethoxy)phenoxy]thieno[2,3-c]pyridine	1299821: Inhibition of full length human recombinant His-tagged CDK8/Cyclin C expressed in baculovirus expression system by fluorescence polarization assay	ic50	0.0011	uM
4-(4-chlorophenoxy)-2-(2H-tetrazol-5-yl)thieno[2,3-c]pyridine	1299821: Inhibition of full length human recombinant His-tagged CDK8/Cyclin C expressed in baculovirus expression system by fluorescence polarization assay	ic50	0.0011	uM
N-(4-propan-2-ylphenyl)-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amine	1921466: Inhibition of CDK8/Cyclin C (unknown origin) by LanthaScreen binding assay	ic50	0.0011	uM
8-[2-amino-3-chloro-5-(1-methyl-2,2-dioxo-3H-2,1-benzothiazol-5-yl)-4-pyridinyl]-2,8-diazaspiro[4.5]decan-1-one	1295749: Binding affinity to CDK8/CDK19 in human 7dF3 cells preincubated for 2 hrs followed by addition 10 uM of beta-oestradiol measured after 24 hrs by luciferase reporter gene assay	ic50	0.0011	uM
[(2S)-2-(4-chlorophenyl)pyrrolidin-1-yl]-(3-methyl-2H-pyrazolo[4,3-b]pyridin-5-yl)methanone	1315916: Inhibition of Alexa647 tracer binding to full length recombinant human His-tagged CDK8/cyclin C expressed in Baculovirus expression system preincubated for 20 mins followed by tracer addition and incubated in dark for 60 mins by FRET-based Lanthascreen assay	ic50	0.0013	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	435903: Binding constant for CDK8 kinase domain	kd	0.0014	uM

CTD chemical–gene interactions

48 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tretinoin	decreases expression	2
Valproic Acid	decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Nanotubes, Carbon	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
bisphenol A	increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	increases expression	1
benzo(e)pyrene	decreases methylation	1
cupric chloride	increases expression	1
methacrylaldehyde	increases abundance, affects cotreatment, decreases expression	1
pinosylvin	decreases expression	1
tamibarotene	affects expression	1
CGP 52608	affects binding, increases reaction	1
tanespimycin	decreases expression	1
corosolic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
bisphenol S	affects cotreatment, decreases methylation	1
Resveratrol	increases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acrolein	affects cotreatment, decreases expression, increases abundance	1
Air Pollutants	decreases expression, increases abundance, affects cotreatment	1
Benzo(a)pyrene	affects methylation	1

ChEMBL screening assays

509 unique, capped per target: 499 binding, 10 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1037101	Binding	Residual activity of CDK8/Cyclin C at 1 uM by microplate scintillation counting	Substituted 2-arylbenzothiazoles as kinase inhibitors: hit-to-lead optimization. — Bioorg Med Chem
CHEMBL1963824	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: CDK8	PubChem BioAssay data set

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1N5	Abcam HeLa CDK8 KO	Cancer cell line	Female
CVCL_B8DG	Abcam HCT 116 CDK8 KO	Cancer cell line	Male
CVCL_B8TY	Abcam MCF-7 CDK8 KO	Cancer cell line	Female
CVCL_B9FN	Abcam A-549 CDK8 KO	Cancer cell line	Male
CVCL_SI43	HAP1 CDK8 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

285 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT05213676	PHASE4	RECRUITING	De-implementing Inhaled Nitric Oxide for Congenital Diaphragmatic Hernia
NCT07247240	PHASE4	NOT_YET_RECRUITING	Efficacy of Inhaled Nitric Oxide in Congenital Diaphragmatic Hernia
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00257946	PHASE3	TERMINATED	Type of Material in Repair of Congenital Diaphragmatic Hernia
NCT03861182	PHASE3	TERMINATED	Contribution of PRF in CDH in Children With Prothetic Patch Closure
NCT06946576	PHASE3	NOT_YET_RECRUITING	Safety and Efficacy of Fetoscopic Endoluminal Tracheal Occlusion in Congenital Diaphragmatic Hernia
NCT07187206	PHASE3	RECRUITING	Safety and Efficacy of FETO in CDH Phase III
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00373438	PHASE2	UNKNOWN	Fetoscopic Tracheal Balloon Occlusion in Left Diaphragmatic Hernia
NCT00966823	PHASE2	TERMINATED	Fetal Tracheal Balloon Study in Diaphragmatic Hernia
NCT01302977	PHASE2	UNKNOWN	Fetal Tracheal Occlusion in Severe Diaphragmatic Hernia: a Randomized Trial
NCT01731509	PHASE2	UNKNOWN	Early FETO for Severe Congenital Diaphragmatic Hernia
NCT02875860	PHASE2	COMPLETED	‘TOTAL’ (Tracheal Occlusion To Accelerate Lung Growth) Trial
NCT02951130	PHASE2	COMPLETED	Milrinone in Congenital Diaphragmatic Hernia
NCT05201144	PHASE2	RECRUITING	A Trial of Phosphodiesterase-5 Inhibitor in Neonatal Congenital Diaphragmatic Hernia (TOP-CDH)
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03526588	PHASE1	TERMINATED	Umbilical Cord Blood Mononuclear Cells for Hypoxic Neurologic Injury in Infants With Congenital Diaphragmatic Hernia (CDH)
NCT02914171	PHASE1	COMPLETED	Study of Autologous Bone Marrow Derived Mononuclear Cells for Treatment of Ebstein Anomaly
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication