CDK12

Summary

CDK12 (cyclin dependent kinase 12, HGNC:24224) is a protein-coding gene on chromosome 17q12, encoding Cyclin-dependent kinase 12 (Q9NYV4). Cyclin-dependent kinase that phosphorylates the C-terminal domain (CTD) of the large subunit of RNA polymerase II (POLR2A), thereby acting as a key regulator of transcription elongation. In precision oncology, CDK12 Mutation confers sensitivity to Olaparib in Castration-resistant Prostate Carcinoma (CIViC Level A); 5 further curated variant–drug associations are listed below. It is a selective cancer dependency (DepMap: 30.2% of cell lines).

Enables RNA polymerase II CTD heptapeptide repeat kinase activity and cyclin binding activity. Involved in several processes, including positive regulation of transcription elongation by RNA polymerase II; protein autophosphorylation; and regulation of MAP kinase activity. Located in nuclear speck. Part of cyclin K-CDK12 complex. Biomarker of gastric adenocarcinoma; hepatocellular carcinoma; and stomach cancer.

Source: NCBI Gene 51755 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Tourette syndrome (No Known Disease Relationship, GenCC)
• GWAS associations: 19
• Clinical variants (ClinVar): 1,764 total — 1 likely-pathogenic
• Druggable target: yes — 17 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 6 curated variant–drug associations
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 9 cancer types
• Cancer dependency (DepMap): dependent in 30.2% of screened cell lines
• MANE Select transcript: NM_016507

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24224
Approved symbol	CDK12
Name	cyclin dependent kinase 12
Location	17q12
Locus type	gene with protein product
Status	Approved
Aliases	CRK7, CRKR, KIAA0904
Ensembl gene	ENSG00000167258
Ensembl biotype	protein_coding
OMIM	615514
Entrez	51755

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 5 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000430627, ENST00000447079, ENST00000558240, ENST00000559663, ENST00000581593, ENST00000581963, ENST00000584336, ENST00000584632, ENST00000585161, ENST00000922307

RefSeq mRNA: 2 — MANE Select: NM_016507 NM_015083, NM_016507

CCDS: CCDS11337, CCDS45666

Canonical transcript exons

ENST00000447079 — 14 exons

Exon	Start	End
ENSE00001121671	39525864	39526316
ENSE00001121680	39524674	39524885
ENSE00001121690	39519956	39520087
ENSE00001121697	39517440	39517556
ENSE00001121703	39515731	39515808
ENSE00001121737	39490557	39490733
ENSE00001201250	39509705	39509761
ENSE00001201272	39470879	39471763
ENSE00001612678	39511529	39511630
ENSE00001696255	39501250	39501439
ENSE00001757901	39494524	39494694
ENSE00002685627	39530604	39534544
ENSE00002688741	39461486	39463117
ENSE00003514777	39492751	39492890

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 96.59.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.3241 / max 302.5122, expressed in 1806 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
160567	18.3288	1801
160568	0.5727	283
160569	0.4226	164

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	96.59	gold quality
sural nerve	UBERON:0015488	95.67	gold quality
secondary oocyte	CL:0000655	94.67	gold quality
colonic epithelium	UBERON:0000397	94.30	gold quality
ganglionic eminence	UBERON:0004023	93.42	gold quality
mucosa of stomach	UBERON:0001199	91.71	gold quality
ventricular zone	UBERON:0003053	91.21	gold quality
calcaneal tendon	UBERON:0003701	90.26	gold quality
adrenal tissue	UBERON:0018303	90.25	gold quality
skin of leg	UBERON:0001511	89.98	gold quality
tonsil	UBERON:0002372	89.78	gold quality
right uterine tube	UBERON:0001302	89.65	gold quality
left ovary	UBERON:0002119	89.57	gold quality
ectocervix	UBERON:0012249	89.51	gold quality
monocyte	CL:0000576	89.33	gold quality
endocervix	UBERON:0000458	89.27	gold quality
right testis	UBERON:0004534	89.24	gold quality
right ovary	UBERON:0002118	89.23	gold quality
skin of abdomen	UBERON:0001416	89.12	gold quality
tendon	UBERON:0000043	89.10	gold quality
right lobe of thyroid gland	UBERON:0001119	89.02	gold quality
left testis	UBERON:0004533	88.94	gold quality
leukocyte	CL:0000738	88.82	gold quality
mononuclear cell	CL:0000842	88.81	gold quality
body of uterus	UBERON:0009853	88.81	gold quality
granulocyte	CL:0000094	88.80	gold quality
vagina	UBERON:0000996	88.69	gold quality
left lobe of thyroid gland	UBERON:0001120	88.66	gold quality
lymph node	UBERON:0000029	88.55	gold quality
rectum	UBERON:0001052	88.48	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-75688	yes	558.10
E-ANND-3	yes	5.53
E-MTAB-6058	no	239.06

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

136 targeting CDK12, 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-8485	100.00	77.57	4731
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-545-3P	99.95	70.74	2783
HSA-LET-7C-3P	99.95	73.42	2862

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 30.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• CRK7 modifies MAP kinases regulation and resistance to estrogen signaling inhibitors in breast cancers. (PMID:19651820)
• Data show that siRNA knockdown of hCDK12 in HeLa cells results in alterations in the CTD phosphorylation state. (PMID:20952539)
• through regulation of expression of DNA damage response genes, CycK/Cdk12 protects cells from genomic instability (PMID:22012619)
• CDK12 interacts with cyclin K and is required to maintain embryonnic stem cell self-renewal. (PMID:22547058)
• Cyclin K1 is the primary cyclin partner for CDK12/CrkRS and it is required for activation of CDK12/CrkRS to phosphorylate the C-terminal domain of RNA Pol II. (PMID:22988298)
• CDK12 has properties that should confirm interest in its use as a biomarker. (PMID:24240700)
• many CDK12 mutations are an unrecognized cause of HR defects in ovarian cancers (PMID:24554720)
• CDK12 plays an important role in cotranscriptional processing of c-FOS transcripts (PMID:25384976)
• CDK12 affects RNA processing events in two distinct ways: Indirectly through generating factor-binding phospho-epitopes on the CTD of elongating RNAPII and directly through binding to specific factors (PMID:25429106)
• CDK12 and CDK13 losses in HCT116 cells preferentially affect expression of DNA damage response. (PMID:25561469)
• Data show that most mutations prevent formation of the cyclin-dependent kinase 12 (Cdk12)/cyclin K (CycK) complex, rendering the kinase inactive. (PMID:25712099)
• Structures of CDK12/CycK complexes solved in the presence of AMP-PNP. (PMID:26597175)
• In Ovarian Cancer patients CDK12 loss is consistently associated with a particular genomic instability pattern characterized by hundreds of tandem duplications (PMID:26787835)
• CDK12 gene amplification can contribute to the pathogenesis of breast cancer. (PMID:28334900)
• BRCA1 downregulation combined with CHK1 inhibition induced excessive amounts of DNA damage, resulting in an inability to complete the S-phase. Therefore, we suggest CHK1 inhibition as a strategy for targeting BRCA1- or CDK12-deficient tumors. (PMID:29025359)
• Data suggest that diagnostic IHC quantification of CDK12 in breast cancer is feasible, with CDK12 absence possibly signifying defective DDR function. (PMID:29133620)
• CDK12 regulates prereplicative complex assembly to promote mammalian cell proliferation. (PMID:29760377)
• Cyclin K expression positively correlates with cell proliferation; knockdown of cyclin K or its cognate kinase CDK12 prevents the assembly of prereplicative complex in the G1 cell cycle phase. (PMID:29760377)
• The challenge is to understand CDK12 as a tumor suppressor well enough to explain how it loss promotes cancer development and how it can intercede to prevent or treat those cancers. (PMID:30319007)
• CDK12 regulates DNA repair genes by suppressing intronic polyadenylation; work clarifies the function of CDK12 and underscores its potential both as a chemotherapeutic target and as a tumour biomarker (PMID:30487607)
• The CDK12-G879V mutation likely results in a nonfunctional CDK12 kinase and chemotherapy susceptibility in lung metastatic sites. (PMID:30617155)
• CDK12 cooperates with mTORC1, and controls a specialized translation network that is essential for mitotic chromosome stability. (PMID:30819820)
• CDK12 inhibition in cancer cells lacking CDK12 mutations results in gene length-dependent elongation defects, inducing premature cleavage and polyadenylation (PCPA) and loss of expression of long (>45 kb) genes, a substantial proportion of which participate in Dna Damage Response. (PMID:30988284)
• Pan-Cancer Analysis of CDK12 Loss-of-Function Alterations and Their Association with the Focal Tandem-Duplicator Phenotype. (PMID:31292271)
• CDK12 is a major oncogenic driver and an actionable target for HER2(+) breast cancer to replace or augment current anti-HER2 therapies. (PMID:31468695)
• CDK12 protein expression in gastric cancer tissues.Positive correlations of CD8(+) cell number and CCL21 mRNA expression with CDK12 level in gastric cancer were identified. (PMID:31523177)
• Clinical Outcomes in Cyclin-dependent Kinase 12 Mutant Advanced Prostate Cancer. (PMID:31640893)
• CDK12 Activity-Dependent Phosphorylation Events in Human Cells. (PMID:31652541)
• CDK12 Promotes Breast Cancer Progression and Maintains Stemness by Activating c-myc/beta -catenin Signaling. (PMID:31744448)
• Lack of evidence for CDK12 as an ovarian cancer predisposing gene. (PMID:32172432)
• Pan-cancer Analysis of CDK12 Alterations Identifies a Subset of Prostate Cancers with Distinct Genomic and Clinical Characteristics. (PMID:32317181)
• CDK12 and PAK2 as novel therapeutic targets for human gastric cancer. (PMID:32483448)
• Low expression of CDK12 in gastric cancer is correlated with advanced stage and poor outcome. (PMID:32534699)
• CDK12: A Potent Target and Biomarker for Human Cancer Therapy. (PMID:32570740)
• Cyclin-dependent kinase 12 (CDK12) in chordoma: prognostic and therapeutic value. (PMID:32691223)
• Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation. (PMID:32804079)
• CDK12 globally stimulates RNA polymerase II transcription elongation and carboxyl-terminal domain phosphorylation. (PMID:32805052)
• CDK12 and HER2 coamplification in two urothelial carcinomas with rapid and aggressive clinical progression. (PMID:33038052)
• CDK12: a potential therapeutic target in cancer. (PMID:33038524)
• BRCA2, ATM, and CDK12 Defects Differentially Shape Prostate Tumor Driver Genomics and Clinical Aggression. (PMID:33414135)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cdk12	ENSDARG00000063726
mus_musculus	Cdk12	ENSMUSG00000003119
rattus_norvegicus	Cdk12	ENSRNOG00000006000

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), CDK8 (ENSG00000132964), CDK7 (ENSG00000134058), CDK4 (ENSG00000135446), CDK9 (ENSG00000136807), CDK15 (ENSG00000138395), CDKL2 (ENSG00000138769), CDK19 (ENSG00000155111), CDK20 (ENSG00000156345), CDK5 (ENSG00000164885), CDK1 (ENSG00000170312), CDK10 (ENSG00000185324), CDKL4 (ENSG00000205111), CDK11B (ENSG00000248333), CDK3 (ENSG00000250506)

Protein

Protein identifiers

Cyclin-dependent kinase 12 — Q9NYV4 (reviewed: Q9NYV4)

Alternative names: Cdc2-related kinase, arginine/serine-rich, Cell division cycle 2-related protein kinase 7, Cell division protein kinase 12

All UniProt accessions (4): A0A590UJE9, Q9NYV4, H0YLT2, J3QSD7

UniProt curated annotations — full annotation on UniProt →

Function. Cyclin-dependent kinase that phosphorylates the C-terminal domain (CTD) of the large subunit of RNA polymerase II (POLR2A), thereby acting as a key regulator of transcription elongation. Regulates the expression of genes involved in DNA repair and is required for the maintenance of genomic stability. Preferentially phosphorylates ‘Ser-5’ in CTD repeats that are already phosphorylated at ‘Ser-7’, but can also phosphorylate ‘Ser-2’. Required for RNA splicing, possibly by phosphorylating SRSF1/SF2. Involved in regulation of MAP kinase activity, possibly leading to affect the response to estrogen inhibitors.

Subunit / interactions. Interacts with CCNL1 and CCNL2. Interacts with CCNK. (Microbial infection) Interacts with human herpes virus 1 (HHV-1) transcriptional regulator ICP22.

Subcellular location. Nucleus. Nucleus speckle.

Tissue specificity. Widely expressed.

Post-translational modifications. Phosphorylation at Thr-893 increases kinase activity.

Disease relevance. Chromosomal aberrations involving CDK12 may be a cause gastric cancer. Deletions within 17q12 region producing fusion transcripts with ERBB2, leading to CDK12-ERBB2 fusion leading to trunctated CDK12 protein not in-frame with ERBB2.

Activity regulation. Inhibited by the ATP analog flavopiridol, purvalanol A, purvalanol B, staurosporine and CR8.

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

Isoforms (3)

UniProt ID	Names	Canonical?
Q9NYV4-1	1	yes
Q9NYV4-2	2
Q9NYV4-3	3

RefSeq proteins (2): NP_055898, NP_057591* (*=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 (134 total): modified residue 38, compositionally biased region 25, helix 17, strand 15, turn 7, sequence conflict 7, region of interest 6, binding site 4, splice variant 4, sequence variant 4, cross-link 3, chain 1, domain 1, active site 1, mutagenesis site 1

Structure

Experimental structures (PDB)

39 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
4NST	X-RAY DIFFRACTION	2.2
8P81	X-RAY DIFFRACTION	2.68
5ACB	X-RAY DIFFRACTION	2.7
9JK1	X-RAY DIFFRACTION	2.72
6CKX	X-RAY DIFFRACTION	2.8
8BU1	X-RAY DIFFRACTION	2.98
7NXK	X-RAY DIFFRACTION	3
6B3E	X-RAY DIFFRACTION	3.06
8BUN	X-RAY DIFFRACTION	3.08
8BU4	X-RAY DIFFRACTION	3.09
8BU2	X-RAY DIFFRACTION	3.13
8BU5	X-RAY DIFFRACTION	3.13
4CXA	X-RAY DIFFRACTION	3.15
4UN0	X-RAY DIFFRACTION	3.15
8BUA	X-RAY DIFFRACTION	3.19
8BUD	X-RAY DIFFRACTION	3.2
8BUQ	X-RAY DIFFRACTION	3.2
8BU7	X-RAY DIFFRACTION	3.25
8BUE	X-RAY DIFFRACTION	3.25
8BUT	X-RAY DIFFRACTION	3.25
8BUS	X-RAY DIFFRACTION	3.26
8BUF	X-RAY DIFFRACTION	3.3
8BUM	X-RAY DIFFRACTION	3.36
8BUL	X-RAY DIFFRACTION	3.4
8BUK	X-RAY DIFFRACTION	3.41
8BUP	X-RAY DIFFRACTION	3.41
8BU3	X-RAY DIFFRACTION	3.42
8BUB	X-RAY DIFFRACTION	3.42
8BU6	X-RAY DIFFRACTION	3.45
6TD3	X-RAY DIFFRACTION	3.46

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NYV4-F1	51.39	0.19

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): 859 (proton acceptor)

Ligand- & substrate-binding residues (4): 733–741; 756; 814–819; 1040

Post-translational modifications (41): 57, 73, 236, 249, 265, 274, 276, 301, 303, 310, 312, 318, 323, 325, 332, 333, 334, 338, 341, 343 …

Mutagenesis-validated functional residues (1):

Position	Phenotype
877	abolishes kinase activity.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-6796648	TP53 Regulates Transcription of DNA Repair Genes
R-HSA-212436	Generic Transcription Pathway
R-HSA-3700989	Transcriptional Regulation by TP53
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)

MSigDB gene sets: 283 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_CELLULAR_RESPONSE_TO_LIPID, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_NEGATIVE_REGULATION_OF_STEM_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_ESTROGEN_RECEPTOR_SIGNALING_PATHWAY, DITTMER_PTHLH_TARGETS_UP, GOBP_REGULATION_OF_INTRACELLULAR_STEROID_HORMONE_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, GGGTGGRR_PAX4_03, GOBP_NEGATIVE_REGULATION_OF_MAPK_CASCADE, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_HORMONE_MEDIATED_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_STEROID_HORMONE_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_INTRACELLULAR_ESTROGEN_RECEPTOR_SIGNALING_PATHWAY

GO Biological Process (12): transcription by RNA polymerase II (GO:0006366), mRNA processing (GO:0006397), RNA splicing (GO:0008380), positive regulation of transcription elongation by RNA polymerase II (GO:0032968), negative regulation of intracellular estrogen receptor signaling pathway (GO:0033147), regulation of MAP kinase activity (GO:0043405), negative regulation of MAPK cascade (GO:0043409), positive regulation of transcription by RNA polymerase II (GO:0045944), cellular response to estrogen stimulus (GO:0071391), negative regulation of stem cell differentiation (GO:2000737), protein phosphorylation (GO:0006468), regulation of cell cycle (GO:0051726)

GO Molecular Function (12): protein kinase activity (GO:0004672), cyclin-dependent protein serine/threonine kinase activity (GO:0004693), ATP binding (GO:0005524), RNA polymerase II CTD heptapeptide repeat kinase activity (GO:0008353), protein kinase binding (GO:0019901), cyclin binding (GO:0030332), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein serine/threonine kinase activity (GO:0004674), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (7): cyclin K-CDK12 complex (GO:0002944), nucleus (GO:0005634), nucleoplasm (GO:0005654), cyclin/CDK positive transcription elongation factor complex (GO:0008024), nuclear speck (GO:0016607), nuclear cyclin-dependent protein kinase holoenzyme complex (GO:0019908), cyclin-dependent protein kinase holoenzyme complex (GO:0000307)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Transcriptional Regulation by TP53	1
RNA Polymerase II Transcription	1
Generic Transcription Pathway	1
Gene expression (Transcription)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA processing	2
protein serine/threonine kinase activity	2
protein kinase activity	2
cyclin-dependent protein kinase holoenzyme complex	2
DNA-templated transcription	1
mRNA metabolic process	1
transcription elongation by RNA polymerase II	1
positive regulation of DNA-templated transcription, elongation	1
regulation of transcription elongation by RNA polymerase II	1
positive regulation of transcription by RNA polymerase II	1
estrogen receptor signaling pathway	1
negative regulation of intracellular steroid hormone receptor signaling pathway	1
regulation of intracellular estrogen receptor signaling pathway	1
MAP kinase activity	1
regulation of protein serine/threonine kinase activity	1
MAPK cascade	1
regulation of MAPK cascade	1
negative regulation of intracellular signal transduction	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
cellular response to hormone stimulus	1
response to estrogen	1
negative regulation of cell differentiation	1
stem cell differentiation	1
regulation of stem cell differentiation	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
kinase binding	1
protein binding	1
nucleoside phosphate binding	1

Protein interactions and networks

STRING

2548 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CDK12	CCNK	O75909	997
CDK12	DDB1	Q16531	927
CDK12	CCNL2	Q96S94	874
CDK12	CCNH	P51946	785
CDK12	BRCA2	P51587	734
CDK12	BRCA1	P38398	709
CDK12	PALB2	Q86YC2	667
CDK12	RAD51C	O43502	667
CDK12	SUPT5H	O00267	665
CDK12	ATM	Q13315	660
CDK12	CCNT1	O60563	658
CDK12	POLR2A	P24928	642
CDK12	K7EN88	K7EN88	640
CDK12	CCNL1	Q9UK58	634
CDK12	RAD51D	O75771	628

IntAct

129 interactions, top by confidence:

A	B	Type	Score
CDK9	CCNT1	psi-mi:“MI:0914”(association)	0.980
CDK13	CCNK	psi-mi:“MI:0914”(association)	0.830
CDK9	AIP	psi-mi:“MI:0914”(association)	0.730
CDK12	CCNK	psi-mi:“MI:0914”(association)	0.690
SPTLC1	SPTLC2	psi-mi:“MI:0914”(association)	0.680
CSNK2B	NMT2	psi-mi:“MI:0914”(association)	0.660
YWHAE	SRSF10	psi-mi:“MI:0914”(association)	0.560
RPS3	ZNF316	psi-mi:“MI:0914”(association)	0.530
MAGEB2	POLRMT	psi-mi:“MI:0914”(association)	0.530
RPL37A	MPHOSPH10	psi-mi:“MI:0914”(association)	0.530
SRPK2	RRP9	psi-mi:“MI:0914”(association)	0.530
AHSP	TTLL4	psi-mi:“MI:0914”(association)	0.530
ABT1	ZNF316	psi-mi:“MI:0914”(association)	0.530
EZH1	EPOP	psi-mi:“MI:0914”(association)	0.530
RPL13	RRP8	psi-mi:“MI:0914”(association)	0.530
SRSF5	CBX6	psi-mi:“MI:0914”(association)	0.530
CCNK	CDC73	psi-mi:“MI:0914”(association)	0.460
CCNK	POLR2A	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
CDK12	PLEC	psi-mi:“MI:0915”(physical association)	0.400
EWSR1	CDK12	psi-mi:“MI:0915”(physical association)	0.370
PRPF40A	CDK12	psi-mi:“MI:0915”(physical association)	0.370
JUN		psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
EGLN3	FAM168B	psi-mi:“MI:0914”(association)	0.350
	SGK1	psi-mi:“MI:0914”(association)	0.350
	TBKBP1	psi-mi:“MI:0914”(association)	0.350
CDC73	BRD4	psi-mi:“MI:0914”(association)	0.350
CCNK	POLR2A	psi-mi:“MI:0914”(association)	0.350

BioGRID (261): CDK12 (Affinity Capture-MS), CDK12 (Affinity Capture-MS), CDK12 (Co-fractionation), CDK12 (Co-fractionation), CDK12 (Co-fractionation), CDK12 (Co-fractionation), CDK12 (Co-fractionation), CDK12 (Proximity Label-MS), CDK12 (Biochemical Activity), CDK12 (Biochemical Activity), CDK12 (Affinity Capture-MS), CDK12 (Affinity Capture-MS), CDK12 (Affinity Capture-MS), CDK12 (Affinity Capture-MS), CDK12 (Affinity Capture-MS)

ESM2 similar proteins: A2A6A1, B0BN49, B0QZF7, D2H526, E1BB50, E9PYH6, E9Q4F7, E9Q6J5, F1Q8W0, O15047, O88453, P30414, P30415, Q01538, Q14AX6, Q17QQ9, Q27450, Q3KPW4, Q3UMU9, Q4V8I5, Q505I5, Q5BKY9, Q5SW79, Q5VZP5, Q62417, Q66648, Q66PJ3, Q6A065, Q6P9P0, Q6UB99, Q7TQC7, Q7Z4V5, Q80U49, Q86VM9, Q8BYK8, Q8C5W0, Q8CFC2, Q8NEY8, Q8R0F5, Q8R2M2

Diamond homologs: A2X6X1, A2XUW1, A8XA58, B5DE93, D2H526, E1BB50, E1BB52, O55076, O60145, O74456, O96821, P00546, P06493, P11440, P13863, P21127, P23111, P23437, P23572, P23573, P24033, P24100, P24788, P24923, P24941, P29618, P29619, P34112, P34117, P34556, P35567, P38973, P39951, P43063, P43450, P46551, P46892, P48734, P48963, P51958

SIGNOR signaling

18 interactions.

A	Effect	B	Mechanism
CDK12	“form complex”	CyclinK/CDK12	binding
CDK12	up-regulates	POLR2A	phosphorylation
CDK12	“up-regulates activity”	POLR2A	phosphorylation
CDK12	“up-regulates activity”	PAK2	phosphorylation
CDK7	“up-regulates activity”	CDK12	phosphorylation
“CAK complex”	“up-regulates activity”	CDK12	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 155 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
Transport of Mature Transcript to Cytoplasm	6	20.9×	9e-06
mRNA Splicing	14	14.1×	1e-10
Peptide chain elongation	12	14.0×	3e-09
Viral mRNA Translation	12	14.0×	3e-09
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	12	13.8×	3e-09
Formation of a pool of free 40S subunits	13	13.3×	1e-09
Selenocysteine synthesis	12	13.2×	3e-09
Eukaryotic Translation Termination	12	13.2×	3e-09

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of mRNA splicing, via spliceosome	5	27.2×	1e-04
RNA splicing, via transesterification reactions	5	22.1×	2e-04
cytoplasmic translation	14	18.4×	2e-11
positive regulation of transcription elongation by RNA polymerase II	7	14.9×	6e-05
regulation of alternative mRNA splicing, via spliceosome	8	13.9×	2e-05
negative regulation of translation	9	12.5×	9e-06
ribosomal small subunit biogenesis	7	11.3×	2e-04
RNA processing	6	9.3×	3e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 9 cancer types — BLCA, CCRCC, CESC, DLBCLNOS, MEL, OVT, PRAD, PROSTATE, STAD.

Clinical variants and AI predictions

ClinVar

1764 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	1047
Likely benign	652
Benign	19

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
431025	NM_016507.4(CDK12):c.2636G>T (p.Gly879Val)	Likely pathogenic

SpliceAI

2377 predictions. Top by Δscore:

Variant	Effect	Δscore
17:39490555:A:AG	acceptor_gain	1.0000
17:39490556:G:GA	acceptor_gain	1.0000
17:39490556:GTCCA:G	acceptor_gain	1.0000
17:39490732:AA:A	donor_gain	1.0000
17:39490734:G:GG	donor_gain	1.0000
17:39492742:A:AG	acceptor_gain	1.0000
17:39492743:C:G	acceptor_gain	1.0000
17:39492748:TA:T	acceptor_loss	1.0000
17:39492749:A:AG	acceptor_gain	1.0000
17:39492749:A:G	acceptor_loss	1.0000
17:39492750:G:GA	acceptor_gain	1.0000
17:39492750:GA:G	acceptor_gain	1.0000
17:39492750:GAA:G	acceptor_gain	1.0000
17:39492750:GAAT:G	acceptor_gain	1.0000
17:39492750:GAATT:G	acceptor_gain	1.0000
17:39492886:CACAG:C	donor_gain	1.0000
17:39492888:CAG:C	donor_gain	1.0000
17:39492888:CAGG:C	donor_loss	1.0000
17:39492891:G:GG	donor_gain	1.0000
17:39492891:GT:G	donor_loss	1.0000
17:39494518:T:TA	acceptor_gain	1.0000
17:39494521:CA:C	acceptor_loss	1.0000
17:39494522:A:AC	acceptor_loss	1.0000
17:39494522:A:AG	acceptor_gain	1.0000
17:39494523:G:GC	acceptor_gain	1.0000
17:39494523:GGA:G	acceptor_gain	1.0000
17:39494523:GGAGA:G	acceptor_gain	1.0000
17:39494690:CAAAG:C	donor_loss	1.0000
17:39494692:AAGGT:A	donor_loss	1.0000
17:39494693:AGGTA:A	donor_loss	1.0000

AlphaMissense

9675 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:39492821:T:A	F727I	1.000
17:39492821:T:C	F727L	1.000
17:39492821:T:G	F727V	1.000
17:39492822:T:C	F727S	1.000
17:39492822:T:G	F727C	1.000
17:39492823:T:A	F727L	1.000
17:39492823:T:G	F727L	1.000
17:39492842:G:A	G734R	1.000
17:39492842:G:C	G734R	1.000
17:39492843:G:A	G734E	1.000
17:39492843:G:T	G734V	1.000
17:39492848:G:A	G736R	1.000
17:39492848:G:C	G736R	1.000
17:39492849:G:A	G736E	1.000
17:39492849:G:C	G736A	1.000
17:39492849:G:T	G736V	1.000
17:39492852:C:T	T737I	1.000
17:39492854:T:C	Y738H	1.000
17:39492854:T:G	Y738D	1.000
17:39492857:G:A	G739S	1.000
17:39492857:G:C	G739R	1.000
17:39492857:G:T	G739C	1.000
17:39492858:G:A	G739D	1.000
17:39492858:G:T	G739V	1.000
17:39492861:A:C	Q740P	1.000
17:39492864:T:A	V741E	1.000
17:39492866:T:G	Y742D	1.000
17:39492869:A:G	K743E	1.000
17:39492871:A:C	K743N	1.000
17:39492871:A:T	K743N	1.000

dbSNP variants (sampled 300 via entrez): RS1000019154 (17:39488780 G>A,C), RS1000065395 (17:39489433 G>T), RS1000073636 (17:39495954 C>G,T), RS1000089695 (17:39520484 G>C), RS1000134611 (17:39488984 G>A), RS1000184648 (17:39512249 C>T), RS1000201380 (17:39515743 G>C), RS1000265078 (17:39507093 T>C), RS1000267589 (17:39508558 G>A,C), RS1000271681 (17:39465889 G>C), RS1000274459 (17:39547050 C>A,G), RS1000307861 (17:39516052 A>C,T), RS1000327393 (17:39554418 T>C), RS1000372444 (17:39500506 G>A), RS1000381769 (17:39461313 CG>C)

Disease associations

OMIM: gene MIM:615514 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
Tourette syndrome	No Known Disease Relationship	Unknown

Mondo (3): hereditary breast ovarian cancer syndrome (MONDO:0003582), lung adenocarcinoma (MONDO:0005061), Tourette syndrome (MONDO:0007661)

Orphanet (2): Hereditary breast and/or ovarian cancer syndrome (Orphanet:145), NON RARE IN EUROPE: Adenocarcinoma of the lung (Orphanet:415268)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST000624_15	Ulcerative colitis	3.000000e-08
GCST003372_58	Glomerular filtration rate (creatinine)	5.000000e-15
GCST003401_22	Glomerular filtration rate in non diabetics (creatinine)	9.000000e-14
GCST003589_1	Bronchial hyperresponsiveness in asthma	3.000000e-20
GCST003790_30	Glomerular filtration rate	9.000000e-06
GCST004292_35	Glomerular filtration rate (creatinine)	3.000000e-15
GCST005312_39	Menopause (age at onset)	2.000000e-09
GCST006436_11	Triglyceride levels	2.000000e-08
GCST006483_60	Lung function (FVC)	1.000000e-08
GCST007344_86	Estimated glomerular filtration rate	2.000000e-24
GCST008058_204	Estimated glomerular filtration rate	2.000000e-63
GCST008059_117	Estimated glomerular filtration rate	2.000000e-55
GCST008060_29	Estimated glomerular filtration rate	9.000000e-06
GCST008062_97	Blood urea nitrogen levels	6.000000e-06
GCST008916_10	Asthma	5.000000e-09
GCST008916_21	Asthma	2.000000e-62
GCST008916_45	Asthma	3.000000e-10
GCST008916_86	Asthma	2.000000e-14
GCST010002_123	Refractive error	1.000000e-24

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause
EFO:0004530	triglyceride measurement
EFO:0004312	vital capacity

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D005879	Tourette Syndrome	C10.228.140.079.898; C10.228.662.825.800; C10.574.500.850; C16.320.400.820; F03.625.992.850

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (8): CHEMBL3559691 (PROTEIN FAMILY), CHEMBL3559692 (SINGLE PROTEIN), CHEMBL4106169 (PROTEIN COMPLEX), CHEMBL4630753 (PROTEIN FAMILY), CHEMBL4879535 (PROTEIN-PROTEIN INTERACTION), CHEMBL5465245 (PROTEIN-PROTEIN INTERACTION), CHEMBL6193761 (PROTEIN-PROTEIN INTERACTION), CHEMBL6196201 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

17 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 57,096 (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
CHEMBL2103840	DINACICLIB	3	2,257
CHEMBL3137331	DEFACTINIB	3	1,229
CHEMBL38380	FASUDIL	3	11,953
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL1276127	INDIRUBIN	2	181
CHEMBL1944698	ZOTIRACICLIB	2	2,915
CHEMBL384304	RG-547	2	93
CHEMBL445813	AT-7519	2	2,614
CHEMBL5199065	ISTISOCICLIB	2	21
CHEMBL14762	SELICICLIB	2	3,787
CHEMBL4462530	ZEMIRCICLIB	2	429
CHEMBL1230607	PHA-793887	1	299
CHEMBL2140408	AMG-900	1	675
CHEMBL296468	BMS-387032	1	2,075
CHEMBL3545083	RGB-286638	1	551
CHEMBL4594423	TP-1287	1	182
CHEMBL5090754	SY-5609	1	54

Clinical evidence (CIViC)

Drug × variant × indication: 6 predictive associations from 6 curated evidence items; also 1 oncogenic.

Variant	Therapy	Indication	Effect	Level	CIViC
CDK12 Mutation	Olaparib	Castration-resistant Prostate Carcinoma	Sensitivity/Response	CIViC A	EID11204
CDK12 Mutation	Talazoparib + Enzalutamide	Castration-resistant Prostate Carcinoma	Sensitivity/Response	CIViC A	EID11735
CDK12 Mutation	Olaparib	Prostate Cancer	Sensitivity/Response	CIViC B	EID7473
CDK12 Loss-of-function	Talazoparib + Olaparib	Breast Carcinoma	Sensitivity/Response	CIViC D	EID12571
CDK12 Loss-of-function	Talazoparib + Olaparib + Rucaparib + Veliparib	Prostate Cancer	Sensitivity/Response	CIViC D	EID12572
CDK12 Loss-of-function	Olaparib	Ovarian Serous Carcinoma	Sensitivity/Response	CIViC D	EID623

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — CRK7 subfamily

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
YJZ5118	Inhibition	7.4	pIC50
CDK12 inhibitor 2	Inhibition	7.28	pIC50
SY-5609	Inhibition	5.77	pIC50

Binding affinities (BindingDB)

155 measured of 259 human assays (259 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[3-fluoro-4-(1-prop-2-enoyl-3,6-dihydro-2H-pyridin-4-yl)phenyl]propanamide	IC50	9 nM	US-10894786: Substituted pyrazole derivatives as selective CDK12/13 inhibitors
2-(6-amino-3-pyridinyl)-9-ethyl-N-[[6-(2-methyl-4-pyridinyl)-3-pyridinyl]methyl]purin-6-amine	IC50	12 nM	US-20250101023: HETEROARYL DERIVATIVE AND USES THEREOF
2-(4-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-3-fluorophenyl)-N-(5- cyclopropyl-1H-pyrazol-3-yl)propanamide	IC50	14 nM	US-10894786: Substituted pyrazole derivatives as selective CDK12/13 inhibitors
9-ethyl-2-pyridin-3-yl-N-[(6-pyridin-3-yl-3-pyridinyl)methyl]purin-6-amine	IC50	16 nM	US-20250101023: HETEROARYL DERIVATIVE AND USES THEREOF
(3R,4R)-4-[[[3-cyclopropyl-7-[(7-phenylimidazo[1,2-a]pyridin-2-yl)methylamino]pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol	IC50	18 nM	US-12473303: 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino methyl]piperidin-3-ol compounds and their therapeutic use
2-(2-aminopyrimidin-5-yl)-9-ethyl-N-[[6-(2-methyl-4-pyridinyl)-3-pyridinyl]methyl]purin-6-amine	IC50	19 nM	US-20250101023: HETEROARYL DERIVATIVE AND USES THEREOF
(3R,4R)-4-[[[7-[(3-methylimidazo[2,1-b][1,3]thiazol-6-yl)methylamino]-3-propan-2-ylpyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol	IC50	20 nM	US-12473303: 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino methyl]piperidin-3-ol compounds and their therapeutic use
(3R,4R)-4-[[[7-[(5,7-dimethylimidazo[1,2-a]pyrimidin-2-yl)methylamino]-3-propan-2-ylpyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol	IC50	21 nM	US-12473303: 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino methyl]piperidin-3-ol compounds and their therapeutic use
(3R,4R)-4-[[[3-ethyl-7-[(5-methylimidazo[1,2-a]pyridin-2-yl)methylamino]pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol	IC50	24 nM	US-12473303: 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino methyl]piperidin-3-ol compounds and their therapeutic use
(3R,4R)-4-[[[7-[(6-chloroimidazo[1,2-a]pyridin-2-yl)methylamino]-3-propan-2-ylpyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol	IC50	26 nM	US-12473303: 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino methyl]piperidin-3-ol compounds and their therapeutic use
(3R,4R)-4-[[[7-[(1-methylbenzimidazol-5-yl)methylamino]-3-propan-2-ylpyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol	IC50	26.9 nM	US-12473303: 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino methyl]piperidin-3-ol compounds and their therapeutic use
(3R,4R)-4-[[[3-cyclopropyl-7-[(5-methoxyimidazo[1,2-a]pyridin-2-yl)methylamino]pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol	IC50	28 nM	US-12473303: 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino methyl]piperidin-3-ol compounds and their therapeutic use
2-(1’-acryloyl-1’,2’,5’,6’-tetrahydro-[2,3’-bipyridin]-5-yl)-N-(5-cyclopropyl-1H- pyrazol-3-yl)propanamide	IC50	30 nM	US-10894786: Substituted pyrazole derivatives as selective CDK12/13 inhibitors
2-(6-amino-3-pyridinyl)-9-ethyl-N-[(6-pyridin-2-yl-3-pyridinyl)methyl]purin-6-amine	IC50	30 nM	US-20250101023: HETEROARYL DERIVATIVE AND USES THEREOF
(3R,4R)-4-[[[3-ethyl-7-[(8-methylimidazo[1,2-a]pyridin-2-yl)methylamino]pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol	IC50	31 nM	US-12473303: 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino methyl]piperidin-3-ol compounds and their therapeutic use
N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[6-(1-prop-2-enoyl-2,5-dihydropyrrol-3-yl)-3-pyridinyl]propanamide	IC50	32 nM	US-10894786: Substituted pyrazole derivatives as selective CDK12/13 inhibitors
N-(5-(3-benzyl-1-((1r,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)-2-(4-(dimethylamino)piperidin-1-yl)phenyl)acrylamide	IC50	32.5 nM	US-20250100994: CDK12/13 COVALENT INHIBITORS OR PHARMACEUTICAL COMPOSITION THEREOF, AND USES THEREOF
N-(5-(3-benzyl-1-(((1r,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)acrylamide	IC50	32.5 nM	US-20250100994: CDK12/13 COVALENT INHIBITORS OR PHARMACEUTICAL COMPOSITION THEREOF, AND USES THEREOF
N-(5-(3-benzyl-1-((1r,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)-2-bromophenyl)acrylamide	IC50	32.5 nM	US-20250100994: CDK12/13 COVALENT INHIBITORS OR PHARMACEUTICAL COMPOSITION THEREOF, AND USES THEREOF
N-(5-(3-benzyl-1-(((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)-2-((S)-3-methylpiperazin-1-yl)phenyl)acrylamide	IC50	32.5 nM	US-20250100994: CDK12/13 COVALENT INHIBITORS OR PHARMACEUTICAL COMPOSITION THEREOF, AND USES THEREOF
N-[5-[benzylcarbamoyl-[4-[(5-cyano-2-pyridinyl)amino]cyclohexyl]amino]-2-[(3S)-3,4-dimethylpiperazin-1-yl]phenyl]prop-2-enamide	IC50	32.5 nM	US-20250100994: CDK12/13 COVALENT INHIBITORS OR PHARMACEUTICAL COMPOSITION THEREOF, AND USES THEREOF
N-(2-(4-acetylpiperazin-1-yl)-5-(3-benzyl-1-((1r,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)phenyl)acrylamide	IC50	32.5 nM	US-20250100994: CDK12/13 COVALENT INHIBITORS OR PHARMACEUTICAL COMPOSITION THEREOF, AND USES THEREOF
N-(5-(3-benzyl-1-((1r,4R)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)-2-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)acrylamide	IC50	32.5 nM	US-20250100994: CDK12/13 COVALENT INHIBITORS OR PHARMACEUTICAL COMPOSITION THEREOF, AND USES THEREOF
N-(5-(3-benzyl-1-((1r,4S)-4-((5-chloropyridin-2-yl)amino)cyclohexyl)ureido)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)acrylamide	IC50	32.5 nM	US-20250100994: CDK12/13 COVALENT INHIBITORS OR PHARMACEUTICAL COMPOSITION THEREOF, AND USES THEREOF
N-(5-(3-benzyl-1-((1r,4S)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)ureido)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)acrylamide	IC50	32.5 nM	US-20250100994: CDK12/13 COVALENT INHIBITORS OR PHARMACEUTICAL COMPOSITION THEREOF, AND USES THEREOF
N-(5-(1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-((S)-1-phenylethyl)ureido)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)acrylamide	IC50	32.5 nM	US-20250100994: CDK12/13 COVALENT INHIBITORS OR PHARMACEUTICAL COMPOSITION THEREOF, AND USES THEREOF
N-(5-(1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(2-fluorobenzyl)ureido)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)acrylamide	IC50	32.5 nM	US-20250100994: CDK12/13 COVALENT INHIBITORS OR PHARMACEUTICAL COMPOSITION THEREOF, AND USES THEREOF
N-(5-(1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(3-fluorobenzyl)ureido)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)acrylamide	IC50	32.5 nM	US-20250100994: CDK12/13 COVALENT INHIBITORS OR PHARMACEUTICAL COMPOSITION THEREOF, AND USES THEREOF
N-(5-(1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-fluorobenzyl)ureido)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)acrylamide	IC50	32.5 nM	US-20250100994: CDK12/13 COVALENT INHIBITORS OR PHARMACEUTICAL COMPOSITION THEREOF, AND USES THEREOF
(3R,4R)-4-[[[7-[(6-fluoroimidazo[1,2-a]pyridin-2-yl)methylamino]-3-propan-2-ylpyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol	IC50	33 nM	US-12473303: 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino methyl]piperidin-3-ol compounds and their therapeutic use
2-(6-(1-acryloyl-2,5-dihydro-1H-pyrrol-3-yl)pyridin-3-yl)-N-(5-cyclopropyl-1H- pyrazol-3-yl)propanamide	IC50	34 nM	US-10894786: Substituted pyrazole derivatives as selective CDK12/13 inhibitors
(3R,4R)-4-[[[3-cyclopropyl-7-[(5-methylimidazo[1,2-a]pyridin-2-yl)methylamino]pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol	IC50	36 nM	US-12473303: 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino methyl]piperidin-3-ol compounds and their therapeutic use
(3R,4R)-4-[[[3-cyclopropyl-7-[(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methylamino]pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol	IC50	37 nM	US-12473303: 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino methyl]piperidin-3-ol compounds and their therapeutic use
(3R,4R)-4-[[[7-[(5-methylimidazo[1,2-a]pyridin-3-yl)methylamino]-3-propan-2-ylpyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol	IC50	38 nM	US-12473303: 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino methyl]piperidin-3-ol compounds and their therapeutic use
(3R,4R)-4-[[[7-[(7-methylimidazo[1,2-a]pyridin-2-yl)methylamino]-3-propan-2-ylpyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol	IC50	38 nM	US-12473303: 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino methyl]piperidin-3-ol compounds and their therapeutic use
(3R,4R)-4-[[[7-[(6-methylimidazo[1,2-a]pyridin-2-yl)methylamino]-3-propan-2-ylpyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol	IC50	40 nM	US-12473303: 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino methyl]piperidin-3-ol compounds and their therapeutic use
(3R,4R)-4-[[[7-[(5-methylimidazo[1,2-a]pyridin-2-yl)methylamino]-3-propan-2-ylpyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol	IC50	40 nM	US-12473303: 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino methyl]piperidin-3-ol compounds and their therapeutic use
(3R,4R)-4-[[[7-[(7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methylamino]-3-propan-2-ylpyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol	IC50	40 nM	US-12473303: 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino methyl]piperidin-3-ol compounds and their therapeutic use
2-(1’-acryloyl-1’,2’,5’,6’-tetrahydro-[2,3’-bipyridin]-5-yl)-N-(5-cyclopropyl-1H- pyrazol-3-yl)butanamide	IC50	41 nM	US-10894786: Substituted pyrazole derivatives as selective CDK12/13 inhibitors
(3R,4R)-4-[[[3-cyclopropyl-7-[[7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]methylamino]pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol	IC50	44 nM	US-12473303: 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino methyl]piperidin-3-ol compounds and their therapeutic use
(3R,4R)-4-[[[3-cyclopropyl-7-[(5,7-dimethylimidazo[1,2-a]pyridin-2-yl)methylamino]pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol	IC50	45 nM	US-12473303: 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino methyl]piperidin-3-ol compounds and their therapeutic use
(3R,4R)-4-[[[3-cyclopropyl-7-[(5-propan-2-yloxyimidazo[1,2-a]pyridin-2-yl)methylamino]pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol	IC50	46 nM	US-12473303: 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino methyl]piperidin-3-ol compounds and their therapeutic use
(3R,4R)-4-[[[3-cyclopropyl-7-[[5-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]methylamino]pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol	IC50	48 nM	US-12473303: 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino methyl]piperidin-3-ol compounds and their therapeutic use
(3R,4R)-4-[[[3-cyclopropyl-7-[[6-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]methylamino]pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol	IC50	48 nM	US-12473303: 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino methyl]piperidin-3-ol compounds and their therapeutic use
(3R,4R)-4-[[[7-(imidazo[1,2-a]pyridin-2-ylmethylamino)-3-propan-2-ylpyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol	IC50	50.2 nM	US-12473303: 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino methyl]piperidin-3-ol compounds and their therapeutic use
9-propan-2-yl-N-[(6-pyridin-3-yl-3-pyridinyl)methyl]-2-pyrimidin-5-ylpurin-6-amine	IC50	51 nM	US-20250101023: HETEROARYL DERIVATIVE AND USES THEREOF
(3R,4R)-4-[[[7-[(8-methylimidazo[1,2-a]pyridin-2-yl)methylamino]-3-propan-2-ylpyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol	IC50	51.7 nM	US-12473303: 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino methyl]piperidin-3-ol compounds and their therapeutic use
2-[[5-[9-propan-2-yl-6-[(6-pyridin-3-yl-3-pyridinyl)methylamino]purin-2-yl]-2-pyridinyl]amino]ethanol	IC50	53 nM	US-20250101023: HETEROARYL DERIVATIVE AND USES THEREOF
2-(6-(1-acryloylpyrrolidin-3-yl)pyridin-3-yl)-N-(5-cyclopropyl-1H-pyrazol-3- yl)propanamide	IC50	55 nM	US-10894786: Substituted pyrazole derivatives as selective CDK12/13 inhibitors
9-ethyl-N-[[6-(2-methyl-4-pyridinyl)-3-pyridinyl]methyl]-2-pyrimidin-5-ylpurin-6-amine	IC50	56 nM	US-20250101023: HETEROARYL DERIVATIVE AND USES THEREOF

ChEMBL bioactivities

1023 potent at pChembl≥5 of 1067 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	CHEMBL5573550
9.00	IC50	1	nM	CHEMBL5567321
8.99	Kd	1.032	nM	CHEMBL3752910
8.99	ED50	1.032	nM	CHEMBL3752910
8.70	IC50	2	nM	CHEMBL5575019
8.66	EC50	2.2	nM	CHEMBL5178057
8.52	IC50	3	nM	CHEMBL5573404
8.52	IC50	3	nM	CHEMBL5572601
8.52	IC50	3	nM	CHEMBL5571201
8.52	IC50	3	nM	DINACICLIB
8.41	EC50	3.9	nM	CHEMBL5184280
8.40	IC50	4	nM	CHEMBL4777061
8.36	EC50	4.4	nM	CHEMBL5200971
8.27	EC50	5.38	nM	CHEMBL6147235
8.26	EC50	5.5	nM	CHEMBL5182667
8.22	IC50	6	nM	CHEMBL4799386
8.22	IC50	6	nM	CHEMBL5420004
8.17	EC50	6.8	nM	CHEMBL5205494
8.16	IC50	6.9	nM	CHEMBL5929886
8.15	IC50	7	nM	DINACICLIB
8.10	IC50	8	nM	CHEMBL5573275
8.05	IC50	9	nM	CHEMBL4792293
8.05	IC50	9	nM	CHEMBL5424163
8.05	EC50	9	nM	CHEMBL5595312
8.00	IC50	10	nM	CHEMBL4797074
8.00	IC50	10	nM	TP-1287
8.00	IC50	10	nM	CHEMBL5571531
8.00	IC50	10	nM	CHEMBL5591253
7.92	IC50	12	nM	CHEMBL4784107
7.92	EC50	12	nM	CHEMBL258721
7.89	IC50	13	nM	CHEMBL4159417
7.85	IC50	14	nM	CHEMBL4783704
7.85	Kd	14	nM	CHEMBL4852083
7.85	IC50	14	nM	CHEMBL4852083
7.85	IC50	14	nM	CHEMBL4649135
7.85	IC50	14.1	nM	CHEMBL4163879
7.82	IC50	15	nM	CHEMBL4791134
7.82	EC50	15	nM	CHEMBL5573487
7.81	EC50	15.5	nM	CHEMBL4877117
7.81	IC50	15.5	nM	CHEMBL6147235
7.80	EC50	16	nM	CHEMBL518800
7.80	EC50	16	nM	CHEMBL1615221
7.79	Kd	16.2	nM	CHEMBL4160662
7.77	EC50	17	nM	CHEMBL461557
7.76	IC50	17.5	nM	CHEMBL6150916
7.75	Kd	18	nM	CHEMBL4868958
7.75	IC50	18	nM	CHEMBL5574515
7.75	EC50	18	nM	CHEMBL5575551
7.71	EC50	19.3	nM	CHEMBL5193459
7.71	IC50	19.4	nM	CHEMBL6151134

PubChem BioAssay actives

246 with measured affinity, of 863 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148043: Binding affinity to human CDK12 incubated for 45 mins by Kinobead based pull down assay	kd	0.0010	uM
2-[(3R)-4-[9-ethyl-6-[(6-pyrazol-1-yl-3-pyridinyl)methylamino]purin-2-yl]morpholin-3-yl]ethanol	2096918: Inhibition of recombinant human CDK12/Cyclin K using RNA Pol II-CTD as substrate preincubated for ~20 mins followed by 33P-ATP addition measured after 120 mins by HotSpot kinase assay	ic50	0.0010	uM
2-[(2S)-1-[6-[[6-(5-amino-3-methylpyrazol-1-yl)-3-pyridinyl]methylamino]-9-ethylpurin-2-yl]piperidin-2-yl]ethanol	2096918: Inhibition of recombinant human CDK12/Cyclin K using RNA Pol II-CTD as substrate preincubated for ~20 mins followed by 33P-ATP addition measured after 120 mins by HotSpot kinase assay	ic50	0.0010	uM
2-[(2S)-1-[9-ethyl-6-[[6-(furan-3-yl)-3-pyridinyl]methylamino]purin-2-yl]piperidin-2-yl]ethanol	2096918: Inhibition of recombinant human CDK12/Cyclin K using RNA Pol II-CTD as substrate preincubated for ~20 mins followed by 33P-ATP addition measured after 120 mins by HotSpot kinase assay	ic50	0.0020	uM
3-benzyl-1-[4-[(5-cyano-2-pyridinyl)amino]cyclohexyl]-1-[4-[4-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]acetyl]piperazin-1-yl]phenyl]urea	1870802: Protac activity at CRBN/CDK12 in human MDA-MB-231 cells assessed as induction of CDK12 degradation incubated for 15 hrs by immunoblotting analysis	ec50	0.0022	uM
2-[(3R)-4-[9-ethyl-6-[[6-(furan-3-yl)-3-pyridinyl]methylamino]purin-2-yl]morpholin-3-yl]ethanol	2096918: Inhibition of recombinant human CDK12/Cyclin K using RNA Pol II-CTD as substrate preincubated for ~20 mins followed by 33P-ATP addition measured after 120 mins by HotSpot kinase assay	ic50	0.0030	uM
2-[(3R)-4-[9-ethyl-6-[[6-(1,3-oxazol-2-yl)-3-pyridinyl]methylamino]purin-2-yl]morpholin-3-yl]ethanol	2096918: Inhibition of recombinant human CDK12/Cyclin K using RNA Pol II-CTD as substrate preincubated for ~20 mins followed by 33P-ATP addition measured after 120 mins by HotSpot kinase assay	ic50	0.0030	uM
2-[(2S)-1-[9-ethyl-6-[(6-pyrazol-1-yl-3-pyridinyl)methylamino]purin-2-yl]piperidin-2-yl]ethanol	2096918: Inhibition of recombinant human CDK12/Cyclin K using RNA Pol II-CTD as substrate preincubated for ~20 mins followed by 33P-ATP addition measured after 120 mins by HotSpot kinase assay	ic50	0.0030	uM
2-[(2S)-1-[3-ethyl-7-[(1-oxidopyridin-1-ium-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-5-yl]piperidin-2-yl]ethanol	2096918: Inhibition of recombinant human CDK12/Cyclin K using RNA Pol II-CTD as substrate preincubated for ~20 mins followed by 33P-ATP addition measured after 120 mins by HotSpot kinase assay	ic50	0.0030	uM
3-benzyl-1-[4-[(5-cyano-2-pyridinyl)amino]cyclohexyl]-1-[4-[4-[2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxyacetyl]piperazin-1-yl]phenyl]urea	1870802: Protac activity at CRBN/CDK12 in human MDA-MB-231 cells assessed as induction of CDK12 degradation incubated for 15 hrs by immunoblotting analysis	ec50	0.0039	uM
3-[4-[4-[benzylcarbamoyl-[4-[(5-cyano-2-pyridinyl)amino]cyclohexyl]amino]phenyl]piperazin-1-yl]-N-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]propanamide	1870802: Protac activity at CRBN/CDK12 in human MDA-MB-231 cells assessed as induction of CDK12 degradation incubated for 15 hrs by immunoblotting analysis	ec50	0.0044	uM
3-benzyl-1-[4-[(5-cyano-2-pyridinyl)amino]cyclohexyl]-1-[4-[4-[2-[[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]amino]acetyl]piperazin-1-yl]phenyl]urea	1870802: Protac activity at CRBN/CDK12 in human MDA-MB-231 cells assessed as induction of CDK12 degradation incubated for 15 hrs by immunoblotting analysis	ec50	0.0055	uM
N-[7-[(3S)-3-[[5-chloro-4-(2-propan-2-ylsulfonylanilino)pyrimidin-2-yl]amino]piperidin-1-yl]heptyl]-2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxyacetamide	2003970: Protac activity at CRBN/CDK12 in human Jurkat cells assessed as reduction of protein degradation measured after 6 hrs by Westernblot analysis	ic50	0.0060	uM
4-[4-[benzylcarbamoyl-[4-[(5-cyano-2-pyridinyl)amino]cyclohexyl]amino]phenyl]-N-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazine-1-carboxamide	1870802: Protac activity at CRBN/CDK12 in human MDA-MB-231 cells assessed as induction of CDK12 degradation incubated for 15 hrs by immunoblotting analysis	ec50	0.0068	uM
2-[(2S)-1-[6-[[6-(3,5-dimethylpyrazol-1-yl)-3-pyridinyl]methylamino]-9-ethylpurin-2-yl]piperidin-2-yl]ethanol	2096918: Inhibition of recombinant human CDK12/Cyclin K using RNA Pol II-CTD as substrate preincubated for ~20 mins followed by 33P-ATP addition measured after 120 mins by HotSpot kinase assay	ic50	0.0080	uM
N-[(5,6-dichloro-1H-benzimidazol-2-yl)methyl]-2-morpholin-4-yl-9-propan-2-ylpurin-6-amine	2116058: Inhibition of 6His-tagged wild type CDK12/cyclin K (unknown origin) infected in insect cells incuabted for 60 mins by TR-FRET assay	ec50	0.0090	uM
N-[7-[(3S)-3-[[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino]piperidin-1-yl]heptyl]-2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxyacetamide	2003969: Protac activity at CRBN/CDK12 in human MOLT-4 cells assessed as reduction of protein degradation by Westernblot analysis	ic50	0.0090	uM
[2-(2-chlorophenyl)-5-hydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]-4-oxochromen-7-yl] dihydrogen phosphate	2075667: Inhibition of CDK12 (unknown origin)	ic50	0.0100	uM
2-[(3R)-4-[6-[[6-(3,5-dimethylpyrazol-1-yl)-3-pyridinyl]methylamino]-9-ethylpurin-2-yl]morpholin-3-yl]ethanol	2096918: Inhibition of recombinant human CDK12/Cyclin K using RNA Pol II-CTD as substrate preincubated for ~20 mins followed by 33P-ATP addition measured after 120 mins by HotSpot kinase assay	ic50	0.0100	uM
5-[4-[3-[6-tert-butylsulfonyl-4-[(4,5-dimethyl-1H-pyrazol-3-yl)amino]quinazolin-7-yl]oxypropyl]piperazin-1-yl]-N-[(3R,5R)-5-[(2,6-difluorophenyl)carbamoyl]-1-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]pyrrolidin-3-yl]pyrazine-2-carboxamide	2115083: Inhibition of CDK12 (unknown origin)	ic50	0.0100	uM
1-(2,6-dichlorophenyl)-6-[[4-(2-hydroxyethoxy)phenyl]methyl]-3-propan-2-yl-5H-pyrazolo[5,4-d]pyrimidin-4-one	2116058: Inhibition of 6His-tagged wild type CDK12/cyclin K (unknown origin) infected in insect cells incuabted for 60 mins by TR-FRET assay	ec50	0.0120	uM
N-[4-(1-methylpyrazol-4-yl)phenyl]-N-[4-(quinazolin-2-ylamino)cyclohexyl]acetamide	1356598: Inhibition of N-terminal FLAG-tagged human full-length CDK12 (1 to 1490 residues)/N-terminal His-tagged CycK (1 to 580 residues) expressed in Sf9 cells assessed as reduction in ATP-dependent ULight-4E-BP1 (Thr37/Thr46) substrate peptide phosphorylation pre-incubated for 60 mins by LANCE Ultra assay	ic50	0.0130	uM
2-[(2S)-1-[6-[(4,5-difluoro-1H-benzimidazol-2-yl)methylamino]-9-ethylpurin-2-yl]piperidin-2-yl]ethanol	2003960: Inhibition of GST-tagged recombinant human CDK12 (696 to 1082 residues) expressed in Insect cell in presence of ATP by Km ATP assay	ic50	0.0140	uM
4-(7-methylsulfonyl-1H-indol-3-yl)-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine	1820463: Inhibition of CDK12/cyclin K (unknown origin) using 5-FAM-labeled peptide as substrate in presence of ATP by mobility shift assay	ic50	0.0150	uM
(2R)-2-[[6-[[4-(5-methylthiophen-2-yl)phenyl]methylamino]-9-propan-2-ylpurin-2-yl]amino]butan-1-ol	2107658: Inhibition of 6His-tagged wild type CDK12/cyclin K (unknown origin) infected in insect cells incubated for 1 hr by TR-FRET assay	ec50	0.0150	uM
(2R)-2-[[9-propan-2-yl-6-[(4-pyridin-2-ylphenyl)methylamino]purin-2-yl]amino]butan-1-ol	2107658: Inhibition of 6His-tagged wild type CDK12/cyclin K (unknown origin) infected in insect cells incubated for 1 hr by TR-FRET assay	ec50	0.0160	uM
(2S)-2-[[9-propan-2-yl-6-[(4-pyridin-2-ylphenyl)methylamino]purin-2-yl]amino]butan-1-ol	2116057: Inhibition of CDK12/cyclin K (unknown origin) in HEK293T cells incubated for 1 hr by TR-FRET assay	ec50	0.0160	uM
3-benzyl-1-[4-[(5-cyano-2-pyridinyl)amino]cyclohexyl]-1-[4-(1-methyl-6-oxo-3-pyridinyl)phenyl]urea	1870803: Binding affinity to human CDK12 (715 to 1052 residues)/CyclinK (1 to 267 residues) expressed in baculovirus infected in Sf9 cells by Biolayer interferometry	kd	0.0162	uM
(2R)-2-[[6-[(4-phenylphenyl)methylamino]-9-propan-2-ylpurin-2-yl]amino]butan-1-ol	2107658: Inhibition of 6His-tagged wild type CDK12/cyclin K (unknown origin) infected in insect cells incubated for 1 hr by TR-FRET assay	ec50	0.0170	uM
(2R)-2-[[6-[3-(3,4-dimethylphenyl)propylamino]-9-propan-2-ylpurin-2-yl]amino]butan-1-ol	2107658: Inhibition of 6His-tagged wild type CDK12/cyclin K (unknown origin) infected in insect cells incubated for 1 hr by TR-FRET assay	ec50	0.0180	uM
2-[[6-[[6-(5-amino-3-methylpyrazol-1-yl)-3-pyridinyl]methylamino]-9-ethylpurin-2-yl]-(2-hydroxyethyl)amino]ethanol	2096918: Inhibition of recombinant human CDK12/Cyclin K using RNA Pol II-CTD as substrate preincubated for ~20 mins followed by 33P-ATP addition measured after 120 mins by HotSpot kinase assay	ic50	0.0180	uM
3-benzyl-1-[4-[(5-cyano-2-pyridinyl)amino]cyclohexyl]-1-[4-[4-[2-[[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]amino]acetyl]piperazin-1-yl]phenyl]urea	1870802: Protac activity at CRBN/CDK12 in human MDA-MB-231 cells assessed as induction of CDK12 degradation incubated for 15 hrs by immunoblotting analysis	ec50	0.0193	uM
N-[(1S,3R)-3-[[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino]-1-methylcyclohexyl]-5-[[(E)-4-(dimethylamino)but-2-enoyl]amino]pyridine-2-carboxamide	1609469: Competitive irreversible inhibition of CDK12/cyclinK (unknown origin) in presence of Km ATP	ic50	0.0200	uM
6-[[[2-[[(2R)-1-hydroxybutan-2-yl]amino]-9-propan-2-ylpurin-6-yl]amino]methyl]-3-pyridin-2-yl-1H-pyridin-2-one	2107658: Inhibition of 6His-tagged wild type CDK12/cyclin K (unknown origin) infected in insect cells incubated for 1 hr by TR-FRET assay	ec50	0.0210	uM
(2R)-2-[[6-[3-(3,4-dichlorophenyl)propylamino]-9-propan-2-ylpurin-2-yl]amino]butan-1-ol	2107658: Inhibition of 6His-tagged wild type CDK12/cyclin K (unknown origin) infected in insect cells incubated for 1 hr by TR-FRET assay	ec50	0.0210	uM
9-ethyl-N-[(6-pyrazol-1-yl-3-pyridinyl)methyl]-2-pyridin-3-ylpurin-6-amine	2096918: Inhibition of recombinant human CDK12/Cyclin K using RNA Pol II-CTD as substrate preincubated for ~20 mins followed by 33P-ATP addition measured after 120 mins by HotSpot kinase assay	ic50	0.0220	uM
2-[(2S)-1-[7-[(4,5-difluoro-1H-benzimidazol-2-yl)methylamino]-3-ethylpyrazolo[1,5-a]pyrimidin-5-yl]piperidin-2-yl]ethanol	2003960: Inhibition of GST-tagged recombinant human CDK12 (696 to 1082 residues) expressed in Insect cell in presence of ATP by Km ATP assay	ic50	0.0220	uM
2-[[6-[[6-(5-amino-3-methylpyrazol-1-yl)-3-pyridinyl]methylamino]-9-ethylpurin-2-yl]amino]ethanol	2096918: Inhibition of recombinant human CDK12/Cyclin K using RNA Pol II-CTD as substrate preincubated for ~20 mins followed by 33P-ATP addition measured after 120 mins by HotSpot kinase assay	ic50	0.0220	uM
4-(1H-indol-3-yl)-N-[(3S)-piperidin-3-yl]-5-(trifluoromethyl)pyrimidin-2-amine	1820463: Inhibition of CDK12/cyclin K (unknown origin) using 5-FAM-labeled peptide as substrate in presence of ATP by mobility shift assay	ic50	0.0240	uM
N-[4-[(3R)-3-[[5-[(5-tert-butyl-1,3-oxazol-2-yl)methylsulfanyl]-1,3-thiazol-2-yl]amino]piperidine-1-carbonyl]phenyl]prop-2-enamide	1652530: Inhibition of human CDK12/cyclin K using Pol2-CTD as substrate by [gamma-33P]ATP-based radioisotope filter binding assay	ic50	0.0250	uM
2-(6-amino-3-pyridinyl)-9-ethyl-N-[[6-(1,3-oxazol-2-yl)-3-pyridinyl]methyl]purin-6-amine	2096918: Inhibition of recombinant human CDK12/Cyclin K using RNA Pol II-CTD as substrate preincubated for ~20 mins followed by 33P-ATP addition measured after 120 mins by HotSpot kinase assay	ic50	0.0270	uM
3-benzyl-1-[4-[(5-cyano-2-pyridinyl)amino]cyclohexyl]-1-(4-piperazin-1-ylphenyl)urea	1870803: Binding affinity to human CDK12 (715 to 1052 residues)/CyclinK (1 to 267 residues) expressed in baculovirus infected in Sf9 cells by Biolayer interferometry	kd	0.0273	uM
(2R)-2-[[9-propan-2-yl-6-[(6-pyridin-4-yl-3-pyridinyl)methylamino]purin-2-yl]amino]butan-1-ol	2107658: Inhibition of 6His-tagged wild type CDK12/cyclin K (unknown origin) infected in insect cells incubated for 1 hr by TR-FRET assay	ec50	0.0280	uM
5-chloro-4-(1H-indol-3-yl)-N-[(3S)-piperidin-3-yl]pyrimidin-2-amine	1820463: Inhibition of CDK12/cyclin K (unknown origin) using 5-FAM-labeled peptide as substrate in presence of ATP by mobility shift assay	ic50	0.0290	uM
5-(2-aminoethylsulfanyl)-3-cyclobutyl-N-[(4-pyridin-2-ylphenyl)methyl]-2H-pyrazolo[4,3-d]pyrimidin-7-amine	1880979: Inhibition of GST-tagged human CDK12/Cyclin K expressed in Sf9 cells using RBER-IRStide peptide as substrate in presence of ATP and [gamma33-P] ATP by radioisotope filter binding assay	ic50	0.0290	uM
4-(4-methylpiperazin-1-yl)-N-[4-(2-methyl-3-propan-2-ylindazol-5-yl)pyrimidin-2-yl]quinolin-7-amine	1771110: Inhibition of human CDK12/cyclin-K incubated for 2 hrs by [gamma-33P]-ATP assay	ic50	0.0291	uM
2-[(2S)-1-[6-[(4,5-difluoro-1H-benzimidazol-2-yl)methylamino]-9-propan-2-ylpurin-2-yl]piperidin-2-yl]ethanol	2003960: Inhibition of GST-tagged recombinant human CDK12 (696 to 1082 residues) expressed in Insect cell in presence of ATP by Km ATP assay	ic50	0.0310	uM
7-methylsulfonyl-3-[2-[[(3S)-piperidin-3-yl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indole-6-carbonitrile	1820463: Inhibition of CDK12/cyclin K (unknown origin) using 5-FAM-labeled peptide as substrate in presence of ATP by mobility shift assay	ic50	0.0330	uM
3-benzyl-1-[4-[(5-cyano-2-pyridinyl)amino]cyclohexyl]-1-[4-[4-[(E)-3-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]prop-2-enoyl]piperazin-1-yl]phenyl]urea	1870802: Protac activity at CRBN/CDK12 in human MDA-MB-231 cells assessed as induction of CDK12 degradation incubated for 15 hrs by immunoblotting analysis	ec50	0.0331	uM
(2R)-2-[[6-[3-(3-methylphenyl)propylamino]-9-propan-2-ylpurin-2-yl]amino]butan-1-ol	2107658: Inhibition of 6His-tagged wild type CDK12/cyclin K (unknown origin) infected in insect cells incubated for 1 hr by TR-FRET assay	ec50	0.0350	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	4
Valproic Acid	affects cotreatment, increases expression, decreases expression, affects expression	4
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
Cadmium Chloride	increases abundance, increases palmitoylation, increases expression, decreases reaction	2
FR900359	affects phosphorylation	1
TAK-243	decreases sumoylation	1
dicrotophos	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	decreases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
manganese chloride	decreases expression, increases abundance	1
diphenylcyclopropenone	decreases expression	1
coumarin	decreases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
entinostat	decreases expression, affects cotreatment	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
veliparib	affects response to substance	1
dinaciclib	decreases activity	1
Resveratrol	affects phosphorylation	1
Fulvestrant	affects response to substance	1
Acetaminophen	increases expression	1
Arsenic	increases expression, affects cotreatment, increases abundance	1
Benzo(a)pyrene	increases methylation	1

ChEMBL screening assays

347 unique, capped per target: 341 binding, 6 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1064257	Binding	Inhibition of CDK in human A2780 cells assessed as reduction of RNAP2 phosphorylation at Ser2 site at 5 uM after 6 hrs by Western bloting	Design, synthesis, and evaluation of 2-methyl- and 2-amino-N-aryl-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amines as ring-constrained 2-anilino-4-(thiazol-5-yl)pyrimidine cyclin-dependent kinase inhibitors. — J Med Chem
CHEMBL5445782	Functional	Affinity Phenotypic Cellular interaction: (In-Cell western blot (using MDA-MB-231 cells)) EUB0001632a CDK12	Affinity Phenotypic Cellular Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_9T25	TOV-3291G	Cancer cell line	Female
CVCL_A1SP	OV-3291	Cancer cell line	Female
CVCL_B1MZ	Abcam HeLa CDK12 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00152750	PHASE4	UNKNOWN	Study of Clonidine on Sleep Architecture in Children With Tourette’s Syndrome (TS) and Comorbid ADHD
NCT00226824	PHASE4	TERMINATED	Safety Study of Galantamine in Tic Disorders
NCT00241176	PHASE4	COMPLETED	Open Label Trial of Aripiprazole in Children and Adolescents With Tourette’s Disorder
NCT00370838	PHASE4	COMPLETED	Comparison of Keppra and Clonidine in the Treatment of Tics
NCT01018056	PHASE4	COMPLETED	Developing New Treatments for Tourette Syndrome: Therapeutic Trials With Modulators of Glutamatergic Neurotransmission
NCT01547000	PHASE4	COMPLETED	Guanfacine in Children With Tic Disorders
NCT03239210	PHASE4	COMPLETED	Effects of Ondansetron in Obsessive-compulsive and Tic Disorders
NCT02562170	PHASE4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
NCT02399566	PHASE4	UNKNOWN	Clinical Trial of Erlotinib and Pemetrexed for Maintenance Treatment in Lung Adenocarcinoma
NCT02804646	PHASE4	UNKNOWN	Endostar Durative Transfusion Combined With Chemotherapy in the Treatment of Advanced Lung Adenocarcinoma
NCT00004376	PHASE3	COMPLETED	Phase III Randomized, Double-Blind, Placebo-Controlled Study of Guanfacine for Tourette Syndrome and Attention Deficit Hyperactivity Disorder
NCT00206323	PHASE3	COMPLETED	A Randomized, Placebo-controlled, Tourette Syndrome Study.
NCT00206336	PHASE3	COMPLETED	An Open-label Study to Determine the Efficacy and Safety of Topiramate in the Treatment of Tourette Syndrome.
NCT00478842	PHASE3	COMPLETED	Pallidal Stimulation and Gilles de la Tourette Syndrome
NCT00681863	PHASE3	TERMINATED	Open-label Extension Study of Pramipexole in the Treatment of Children and Adolescents With Tourette Syndrome
NCT01501695	PHASE3	COMPLETED	Phase III Study of 5LGr to Treat Tic Disorder
NCT03087201	PHASE3	COMPLETED	CANNAbinoids in the Treatment of TICS (CANNA-TICS)
NCT03487783	PHASE3	COMPLETED	Aripiprazole Oral Solution in the Treatment of Children and Adolescents With Tourette’s Syndrome
NCT03567291	PHASE3	TERMINATED	Evaluation of Safety and Tolerability of Long-term TEV-50717 (Deutetrabenazine) for Treatment of Tourette Syndrome in Children and Adolescents
NCT03571256	PHASE3	COMPLETED	A Study to Test if TEV-50717 is Effective in Relieving Tics Associated With Tourette Syndrome (TS)
NCT06021522	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate Long-term Safety of Ecopipam Tablets in Children, Adolescents and Adults With Tourette’s Disorder
NCT00673335	PHASE3	COMPLETED	Letrozole in Preventing Breast Cancer in Postmenopausal Women With a BRCA1 or BRCA2 Mutation
NCT00685256	PHASE3	COMPLETED	Standard Genetic Counseling With or Without a Decision Guide in Improving Communication Between Mothers Undergoing BRCA1/2 Testing and Their Minor-Age Children
NCT03162276	PHASE3	UNKNOWN	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00002852	PHASE3	COMPLETED	Surgery With or Without Chemotherapy in Treating Patients With Stage I Non-small Cell Lung Cancer
NCT00005838	PHASE3	COMPLETED	Combination Chemotherapy Plus Radiation Therapy With or Without AE-941 in Treating Patients With Stage III Non-small Cell Lung Cancer That Cannot Be Removed By Surgery
NCT00020709	PHASE3	COMPLETED	Combination Chemotherapy and Radiation Therapy With or Without Gefitinib in Treating Patients With Stage III Non-Small Cell Lung Cancer That Cannot Be Removed By Surgery
NCT00049543	PHASE3	COMPLETED	Gefitinib in Treating Patients With Stage IB, II, or IIIA Non-small Cell Lung Cancer That Was Completely Removed by Surgery
NCT00946712	PHASE3	TERMINATED	S0819: Carboplatin and Paclitaxel With or Without Bevacizumab and/or Cetuximab in Treating Patients With Stage IV or Recurrent Non-Small Cell Lung Cancer
NCT01798485	PHASE3	TERMINATED	A Phase 3 Study of Ganetespib in Combination With Docetaxel Versus Docetaxel Alone in Patients With Advanced NSCLC
NCT02011997	PHASE3	UNKNOWN	Comparison of cVATS Segmentectomy Versus Lobectomy for Lung Adenocarcinoma in Situ and With Microinvasion
NCT03391869	PHASE3	ACTIVE_NOT_RECRUITING	Nivolumab and Ipilimumab With or Without Local Consolidation Therapy in Treating Patients With Stage IV Non-Small Cell Lung Cancer
NCT03676192	PHASE3	COMPLETED	To Compare Efficacy and Safety of CT-P16 and European Union-Approved Avastin as First-Line Treatment for Metastatic or Recurrent Non-Squamous Non-Small Cell Lung Cancer
NCT04339218	PHASE3	RECRUITING	Cryoablation in Combination (or Not) With Pembrolizumab and Pemetrexed-carboplatin in 1st-line Treatment for Patients With Metastatic Lung Adenocarcinoma
NCT05204758	PHASE3	COMPLETED	Prophylactic TCM for Mitigation of EGFR-TKI Related Dermatological Adverse Effect
NCT05717803	PHASE3	RECRUITING	Segmentectomy for Ground Glass-dominant Invasive Lung Cancer (ECTOP-1012)
NCT05943795	PHASE3	ACTIVE_NOT_RECRUITING	A Clinical Study of SI-B001 Combined With Docetaxel in the Treatment of Non-small Cell Lung Adenocarcinoma and Lung Squamous Cell Carcinoma
NCT06031181	PHASE3	RECRUITING	Sublobar Resection for Adenocarcinoma in Situ/Minimally Invasive Adenocarcinoma Diagnosed by Intraoperative Frozen Section (ECTOP-1019)
NCT06031246	PHASE3	RECRUITING	Selective Lymph Node Dissection for cT1N0M0 Invasive NSCLC With CTR>0.5 Located in the Apical Segment (ECTOP-1018)
NCT06634966	PHASE3	RECRUITING	Segmentectomy for Solid-dominant Lung Cancer