CDK9

Summary

CDK9 (cyclin dependent kinase 9, HGNC:1780) is a protein-coding gene on chromosome 9q34.11, encoding Cyclin-dependent kinase 9 (P50750). Protein kinase involved in the regulation of transcription. It is a common-essential gene (DepMap: required in 99.3% of cancer cell lines).

The protein encoded by this gene is a member of the cyclin-dependent protein kinase (CDK) family. CDK family members are highly similar to the gene products of S. cerevisiae cdc28, and S. pombe cdc2, and known as important cell cycle regulators. This kinase was found to be a component of the multiprotein complex TAK/P-TEFb, which is an elongation factor for RNA polymerase II-directed transcription and functions by phosphorylating the C-terminal domain of the largest subunit of RNA polymerase II. This protein forms a complex with and is regulated by its regulatory subunit cyclin T or cyclin K. HIV-1 Tat protein was found to interact with this protein and cyclin T, which suggested a possible involvement of this protein in AIDS.

Source: NCBI Gene 1025 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary breast carcinoma (Limited, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 56 total — 1 pathogenic
• Druggable target: yes — 62 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 99.3% of screened cell lines (common-essential)
• MANE Select transcript: NM_001261

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1780
Approved symbol	CDK9
Name	cyclin dependent kinase 9
Location	9q34.11
Locus type	gene with protein product
Status	Approved
Aliases	PITALRE, C-2k, TAK
Ensembl gene	ENSG00000136807
Ensembl biotype	protein_coding
OMIM	603251
Entrez	1025

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding_CDS_not_defined, 2 protein_coding

ENST00000373264, ENST00000421939, ENST00000480353, ENST00000491521, ENST00000498339

RefSeq mRNA: 1 — MANE Select: NM_001261 NM_001261

CCDS: CCDS6879

Canonical transcript exons

ENST00000373264 — 7 exons

Exon	Start	End
ENSE00000984619	127788544	127788692
ENSE00001251705	127786034	127786240
ENSE00001814236	127789178	127790792
ENSE00003577785	127786701	127786782
ENSE00003605823	127787947	127788113
ENSE00003627304	127787518	127787608
ENSE00003664039	127788214	127788385

Expression profiles

Bgee: expression breadth ubiquitous, 218 present calls, max score 98.33.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.3287 / max 252.8718, expressed in 1816 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
98664	18.5873	1814
98662	4.0802	1451
98661	0.9049	417
98663	0.7563	456

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	98.33	gold quality
left ovary	UBERON:0002119	98.19	gold quality
right ovary	UBERON:0002118	98.00	gold quality
sural nerve	UBERON:0015488	97.51	gold quality
left uterine tube	UBERON:0001303	97.39	gold quality
mucosa of stomach	UBERON:0001199	97.37	gold quality
tibial nerve	UBERON:0001323	97.23	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.21	gold quality
adenohypophysis	UBERON:0002196	97.19	gold quality
body of uterus	UBERON:0009853	97.14	gold quality
endocervix	UBERON:0000458	96.93	gold quality
left adrenal gland cortex	UBERON:0035825	96.78	gold quality
left adrenal gland	UBERON:0001234	96.64	gold quality
cerebellar hemisphere	UBERON:0002245	96.61	gold quality
right adrenal gland cortex	UBERON:0035827	96.52	gold quality
right lung	UBERON:0002167	96.50	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.41	gold quality
right adrenal gland	UBERON:0001233	96.40	gold quality
cerebellar cortex	UBERON:0002129	96.38	gold quality
granulocyte	CL:0000094	96.37	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.35	gold quality
lower esophagus	UBERON:0013473	96.34	gold quality
right frontal lobe	UBERON:0002810	96.33	gold quality
gall bladder	UBERON:0002110	96.17	gold quality
muscle layer of sigmoid colon	UBERON:0035805	96.07	gold quality
ectocervix	UBERON:0012249	95.93	gold quality
right lobe of thyroid gland	UBERON:0001119	95.81	gold quality
right coronary artery	UBERON:0001625	95.75	gold quality
upper lobe of left lung	UBERON:0008952	95.75	gold quality
left lobe of thyroid gland	UBERON:0001120	95.71	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.96

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

8 targets.

Target	Regulation
ANKRD37
COL1A1
HES1	Activation
HNRNPH1
MAGI1
STC2
UHMK1
VIM

Upstream regulators (CollecTRI, top): CEBPB, DDIT3, MYBL2, NCOR1, NFKB, TBXT, TP53

miRNA regulators (miRDB)

47 targeting CDK9, 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-3163	100.00	77.23	8605
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-1825	99.72	68.11	1089
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-199A-5P	99.51	69.71	1107
HSA-MIR-199B-5P	99.51	69.74	1098
HSA-MIR-5571-5P	99.49	66.99	1764
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-519D-5P	99.41	69.30	2057
HSA-MIR-532-3P	99.34	65.76	1195
HSA-MIR-8065	99.19	70.38	1289
HSA-MIR-6797-3P	99.17	66.94	668
HSA-MIR-4758-3P	99.12	63.96	869

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.3% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• phosphorylates hSpt5 (PMID:11575923)
• P-TEFb containing cyclin K and Cdk9 can activate transcription via RNA. (PMID:11884399)
• Physical interaction between pRb and cdk9/cyclinT2 complex. (PMID:12037672)
• CDK9 has the intrinsic property to shuttle between nucleus and cytoplasm, and enhanced expression of cyclin T1 promotes its nuclear localization. (PMID:12115727)
• The interaction of cdk9 with the NF-kappaB factors can control HIV-1 transcription. (PMID:12173051)
• chimeras between kinase-inactive mutant Cdk9 and truncated cyclin T1 proteins efficiently inhibit Tat transactivation and human immunodeficiency virus gene expression (PMID:12368330)
• interaction with gp130 (PMID:12386808)
• Positive transcription elongation factor b (P-TEFb) comprises a cyclin (T1 or T2) and a kinase, cyclin-dependent kinase 9 (CDK9), which phosphorylates the carboxyl-terminal domain of RNA polymerase II (PMID:12832472)
• CDK9 is constitutively expressed throughout the cell cycle, and its steady-state expression is independent of SKP2 (PMID:12861003)
• Fusion of the PML coiled-coil domain to Cdk9 forms high MW complexes to which cyclin T1 is recruited. The CC-Cdk9 chimera effectively inhibits HIV-1 Tat activation. Expression of CC-Cdk9 inhibits cell proliferation, as shown by colony-formation assay. (PMID:12894230)
• major portion of nuclear P-TEFb is sequestered and inactivated by the coordinated actions of the 7SK snRNA (PMID:14627702)
• RNAi-mediated gene silencing of P-TEFb in HeLa cells was not lethal and inhibited Tat transactivation and HIV-1 replication in host cells (PMID:14963154)
• review of work indicating under some circumstances TAK/P-TEFb is likely to be limiting for HIV replication in CD4+ T cells and macrophages; review of mechanisms of regulation of the TAK/P-TEFb subunits in these cell types (PMID:15049426)
• Cdk9 is a component of the elongation factor P-TEFb, in the STAT3-mediated expression of p21waf1. (PMID:15286705)
• functional differences between the 42k and 55k isoforms of Cdk9 are likely to depend on access to substrates based on their differential subcellular localization and expression patterns (PMID:15452830)
• Review. Cdk9 has dual transcriptional roles in hypertrophic growth and mitochondrial dysfunction in cardiac myocytes. (PMID:15514168)
• CDK9 mediates TNF-alpha-induced MMP-9 transcription (PMID:15528190)
• role in regulation of HIV-1 transcription elongation and histone methylation. (PMID:15564463)
• HEXIM1 and HEXIM2 maintain the balance between active and inactive forms of P-TEFb, a heterodimeric complex composed of cyclin-dependent kinase 9 and cyclin T. (PMID:15713661)
• Cdk9/Cyclin T1 complex is required for neuron differentiation induced by retinoic acid; in neuroblastoma and primary neuroectodermal tumor tumor Cdk9 is more expressed the more differentiated the tumor is. (PMID:15753651)
• requirement of ICP22 and the U(L)13 protein kinase of HSV-1 in the posttranslational modification of RNA POL II (PMID:15890914)
• Analysis of T-loop phosphorylation in Cdk9 indicated that phosphorylation of Thr(186), but not Ser(175), was essential for kinase activity. (PMID:15965233)
• Existence of a feedback-loop between p53 and cdk9, pinpointing a novel mechanism by which p53 regulates the basal transcriptional machinery. (PMID:16741955)
• The results establish that cdk9/cyclin T2a-mediated coactivation of MyoD depends on serine 37 phosphorylation. (PMID:16841087)
• These data link the P-TEFb equilibrium to the intracellular transcriptional demand and proliferative/differentiated states of cells. (PMID:16980611)
• Our data suggest that Tat-C/EBPbeta association is mediated through cdk9, and that phosphorylated C/EBPbeta may influence AIDS progression by increasing expression of HIV-1 genes. (PMID:17251582)
• Cdk9/Cyclin T1 complex may be important in the activation/differentiation program of lymphoid cells and that its upregulation may contribute to malignant transformation. (PMID:17352406)
• These results suggest that acetylation of CDK9 is an important posttranslational modification that is involved in regulating P-TEFb transcriptional elongation function. (PMID:17452463)
• Upon induction of NF-kappaB, a subset of target genes is regulated differentially by either P-TEFb or DSIF.[P-TEFb, DSIF] (PMID:17502349)
• K-cyclin/Cdk9 interaction greatly enhanced the kinase activity of Cdk9 toward p53. (PMID:17942552)
• an IL-6-inducible STAT3 and CDK9 binding to the proximal gamma-FBG promoter as well as increased loading of RNA Pol II (PMID:17956865)
• Parvin-beta might influence breast cancer progression (PMID:17998334)
• while the P-TEFb level remains constant, the Brd4-P-TEFb interaction increases dramatically in cells progressing from late mitosis to early G(1). (PMID:18039861)
• This data suggests an active role for the Cdk9/Cyclin T1 complex during lymphoid differentiation through germinal center reaction. (PMID:18205180)
• TATA-box element mediates the assembly of processive transcription complexes responsive to CDK9 and that specific combinations of upstream activation binding sites contribute to the recruitment of these complexes (PMID:18218627)
• GCN5 & P/CAF regulate CDK9 function by specifically acetylating the catalytic core of the enzyme especially a Lys needed for ATP coordination & the phosphotransfer reaction. Acetylation markedly reduces both the kinase function & transcriptional activity. (PMID:18250157)
• PP2B and PP1alpha cooperatively disrupt 7SK snRNP to release P-TEFb for transcription in response to Ca2+ signaling. (PMID:18483222)
• Study shows that CDK9/CycT1 autophosphorylates on Thr186 in the activation segment and three C-terminal phosphorylation sites; autophosphorylation on all sites occurs in cis. (PMID:18566585)
• The authors conclude that cdk9 plays a critical role in the optimization of expression of genes regulated by ICP22 and that one function of cdk9 in HSV-1-infected cells may be to bring ICP22 into the RNA Pol II transcriptional complex. (PMID:18753202)
• contribution of Cdk9 activity to megakaryocytic differentiation (PMID:18780834)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cdk9	ENSDARG00000044811
mus_musculus	Cdk9	ENSMUSG00000009555
rattus_norvegicus	Cdk9	ENSRNOG00000022586
drosophila_melanogaster	Cdk9	FBGN0019949
caenorhabditis_elegans	cdk-9	WBGENE00000410

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), 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 9 — P50750 (reviewed: P50750)

Alternative names: C-2K, Cell division cycle 2-like protein kinase 4, Cell division protein kinase 9, Serine/threonine-protein kinase PITALRE, Tat-associated kinase complex catalytic subunit

All UniProt accessions (2): P50750, X6RE90

UniProt curated annotations — full annotation on UniProt →

Function. Protein kinase involved in the regulation of transcription. Member of the cyclin-dependent kinase pair (CDK9/cyclin-T) complex, also called positive transcription elongation factor b (P-TEFb), which facilitates the transition from abortive to productive elongation by phosphorylating the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAP II) POLR2A, SUPT5H and RDBP. This complex is inactive when in the 7SK snRNP complex form. Phosphorylates EP300, MYOD1, RPB1/POLR2A and AR and the negative elongation factors DSIF and NELFE. Regulates cytokine inducible transcription networks by facilitating promoter recognition of target transcription factors (e.g. TNF-inducible RELA/p65 activation and IL-6-inducible STAT3 signaling). Promotes RNA synthesis in genetic programs for cell growth, differentiation and viral pathogenesis. P-TEFb is also involved in cotranscriptional histone modification, mRNA processing and mRNA export. Modulates a complex network of chromatin modifications including histone H2B monoubiquitination (H2Bub1), H3 lysine 4 trimethylation (H3K4me3) and H3K36me3; integrates phosphorylation during transcription with chromatin modifications to control co-transcriptional histone mRNA processing. Also catalyzes phosphorylation of histone H1.4 (H1-4) at Ser-187’ (H1.4S187Ph), a modification associated with transcription activation. The CDK9/cyclin-K complex has also a kinase activity towards CTD of RNAP II and can substitute for CDK9/cyclin-T P-TEFb in vitro. Replication stress response protein; the CDK9/cyclin-K complex is required for genome integrity maintenance, by promoting cell cycle recovery from replication arrest and limiting single-stranded DNA amount in response to replication stress, thus reducing the breakdown of stalled replication forks and avoiding DNA damage. In addition, probable function in DNA repair of isoform 2 via interaction with KU70/XRCC6. Promotes cardiac myocyte enlargement. RPB1/POLR2A phosphorylation on ‘Ser-2’ in CTD activates transcription. AR phosphorylation modulates AR transcription factor promoter selectivity and cell growth. DSIF and NELF phosphorylation promotes transcription by inhibiting their negative effect. The phosphorylation of MYOD1 enhances its transcriptional activity and thus promotes muscle differentiation. Catalyzes phosphorylation of KAT5, promoting KAT5 recruitment to chromatin and histone acetyltransferase activity.

Subunit / interactions. Component of the super elongation complex (SEC), at least composed of EAF1, EAF2, CDK9, MLLT3/AF9, AFF (AFF1 or AFF4), the P-TEFb complex and ELL (ELL, ELL2 or ELL3). Associates with CCNT1/cyclin-T1, CCNT2/cyclin-T2 (isoform A and isoform B) or CCNK/cyclin-K to form active P-TEFb. P-TEFb forms a complex with AFF4/AF5Q31 and is part of the super elongation complex (SEC). Component of a complex which is composed of at least 5 members: HTATSF1/Tat-SF1, P-TEFb complex, RNA pol II, SUPT5H and NCL/nucleolin. Associates with UBR5 and forms a transcription regulatory complex composed of CDK9, RNAP II, UBR5 and TFIIS/TCEA1 that can stimulate target gene transcription (e.g. gamma fibrinogen/FGG) by recruiting their promoters. Component of the 7SK snRNP inactive complex which is composed of at least 8 members: P-TEFb (composed of CDK9 and CCNT1/cyclin-T1), HEXIM1, HEXIM2, LARP7, BCDIN3, SART3 proteins and 7SK and U6 snRNAs. This inactive 7SK snRNP complex can also interact with NCOR1 and HDAC3, probably to regulate CDK9 acetylation. Release of P-TEFb from P-TEFb/7SK snRNP complex requires both PP2B to transduce calcium Ca(2+) signaling in response to stimuli (e.g. UV or hexamethylene bisacetamide (HMBA)) and PPP1CA to dephosphorylate Thr-186. This released P-TEFb remains inactive in the pre-initiation complex with BRD4 until new Thr-186 phosphorylation occurs after the synthesis of a short RNA. Interacts with BRD4; to target chromatin binding. Interacts with JMJD6. Interacts with activated nuclear STAT3 and RELA/p65. Binds to AR and MYOD1. Forms a complex composed of CDK9, CCNT1/cyclin-T1, EP300 and GATA4 that stimulates hypertrophy in cardiomyocytes. The large PER complex involved in the repression of transcriptional termination is composed of at least PER2, CDK9, DDX5, DHX9, NCBP1 and POLR2A. Interacts with HSF1. Interacts with TBX21. Isoform 3: binds to KU70/XRCC6. Interacts with WDR43. Interacts with ZMYND8; the association appears to occur between homodimeric ZMYND8 and the activated form of the P-TEFb complex. (Microbial infection) Interacts with the acidic/proline-rich region of HIV-1 and HIV-2 Tat via T-loop region and is thus required for HIV to hijack host transcription machinery during its replication through cooperative binding to viral TAR RNA. (Microbial infection) Interacts with human herpes virus 1 (HHV-1) protein ICP22; this interaction blocks the recruitment of positive transcription elongation factor b (P-TEFb) to the viral promoter.

Subcellular location. Nucleus. Cytoplasm. PML body.

Tissue specificity. Ubiquitous.

Post-translational modifications. Autophosphorylation at Thr-186, Ser-347, Thr-350, Ser-353, Thr-354 and Ser-357 triggers kinase activity by promoting cyclin and substrate binding (e.g. HIV TAT) upon conformational changes. Thr-186 phosphorylation requires the calcium Ca(2+) signaling pathway, including CaMK1D and calmodulin. This inhibition is relieved by Thr-29 dephosphorylation. However, phosphorylation at Thr-29 is inhibitory within the HIV transcription initiation complex. Phosphorylation at Ser-175 inhibits kinase activity. Can be phosphorylated on either Thr-362 or Thr-363 but not on both simultaneously. Dephosphorylation of Thr-186 by PPM1A and PPM1B blocks CDK9 activity and may lead to CDK9 proteasomal degradation. However, PPP1CA-mediated Thr-186 dephosphorylation is required to release P-TEFb from its inactive P-TEFb/7SK snRNP complex. Dephosphorylated at Ser-347 by the PNUTS-PP1 complex during RNA polymerase II transcription pause-release. Dephosphorylation of C-terminus Thr and Ser residues by protein phosphatase-1 (PP1) triggers CDK9 activity, contributing to the activation of HIV-1 transcription. N6-acetylation of Lys-44 promotes kinase activity, whereas acetylation of both Lys-44 and Lys-48 mediated by PCAF/KAT2B and GCN5/KAT2A reduces kinase activity. The acetylated form associates with PML bodies in the nuclear matrix and with the transcriptionally silent HIV-1 genome; deacetylated upon transcription stimulation. Deacetylated by SIRT7, promoting the kinase activity and subsequent ‘Ser-2’ phosphorylation of the C-terminal domain (CTD) of RNA polymerase II. Polyubiquitinated and thus activated by UBR5. This ubiquitination is promoted by TFIIS/TCEA1 and favors ‘Ser-2’ phosphorylation of RPB1/POLR2A CTD.

Disease relevance. Chronic activation of CDK9 causes cardiac myocyte enlargement leading to cardiac hypertrophy and confers predisposition to heart failure.

Activity regulation. Inhibited by CDKI-71, CR8, GPC-286199, AG-024322, flavopiridol (alvocidib), RBG-286147, anilinopyrimidine 32, arylazopyrazole 31b, indirubin 3’-monoxime, meriolin 3,P276-00, olomoucine II, pyrazolotriazine, meriolin, variolin, thiazolyl-pyrimidine, thiazolyl-pyrimidine, indirubin-30-monoxime, ZK 304709, AG-012986, AT7519, R547, RGB-286638, imidazole pyrimidine, EXEL-3700, EXEL-8647, 5,6-dichloro-1-b-ribofur-anosyl-benzimidazole (DRB), P276-00, roscovitine (seliciclib, CYC202) and SNS-032 (BMS-387032). Activation by Thr-186 phosphorylation is calcium Ca(2+) signaling pathway-dependent; actively inactivated by dephosphorylation mediated by PPP1CA, PPM1A and PPM1B. Reversibly repressed by acetylation at Lys-44 and Lys-48.

Induction. By replication stress, in chromatin. Probably degraded by the proteasome upon Thr-186 dephosphorylation.

Miscellaneous. CDK9 inhibition contributes to the anticancer activity of most CDK inhibitors under clinical investigation. As a retroviruses target during the hijack of host transcription (e.g. HIV), CDK9 inhibitors might become specific antiretroviral agents. May be a target for cardiac hypertrophy future treatments. May also be a target in anti-inflammatory therapy in innate immunity and systemic inflammation.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P50750-1	1	yes
P50750-2	2

RefSeq proteins (1): NP_001252* (*=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 (75 total): helix 20, strand 15, modified residue 13, mutagenesis site 10, binding site 4, sequence variant 3, region of interest 2, turn 2, chain 1, domain 1, splice variant 1, sequence conflict 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

28 structures.

PDB	Method	Resolution (Å)
3MI9	X-RAY DIFFRACTION	2.1
3BLH	X-RAY DIFFRACTION	2.48
3BLR	X-RAY DIFFRACTION	2.8
3MY1	X-RAY DIFFRACTION	2.8
7NWK	X-RAY DIFFRACTION	2.81
3BLQ	X-RAY DIFFRACTION	2.9
4OR5	X-RAY DIFFRACTION	2.9
4IMY	X-RAY DIFFRACTION	2.94
3TN8	X-RAY DIFFRACTION	2.95
4BCH	X-RAY DIFFRACTION	2.96
3LQ5	X-RAY DIFFRACTION	3
3MIA	X-RAY DIFFRACTION	3
4OGR	X-RAY DIFFRACTION	3
4BCF	X-RAY DIFFRACTION	3.01
4BCG	X-RAY DIFFRACTION	3.08
4BCI	X-RAY DIFFRACTION	3.1
6W9E	X-RAY DIFFRACTION	3.1
4BCJ	X-RAY DIFFRACTION	3.16
6GZH	X-RAY DIFFRACTION	3.17
3TNH	X-RAY DIFFRACTION	3.2
4EC9	X-RAY DIFFRACTION	3.21
3TNI	X-RAY DIFFRACTION	3.23
6Z45	X-RAY DIFFRACTION	3.37
6CYT	X-RAY DIFFRACTION	3.5
4EC8	X-RAY DIFFRACTION	3.6
8I0L	X-RAY DIFFRACTION	3.6
8K5R	X-RAY DIFFRACTION	3.75
5L1Z	X-RAY DIFFRACTION	5.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P50750-F1	86.94	0.72

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): 149 (proton acceptor)

Ligand- & substrate-binding residues (4): 25–33; 48; 104–106; 167

Post-translational modifications (13): 44, 48, 175, 186, 347, 350, 353, 354, 357, 362, 363, 35, 54

Mutagenesis-validated functional residues (10):

Position	Phenotype
44	impaired kinase and transcriptional elongation activities, but normal cyclin t1 and hexim1 binding.
48	mimics acetylation; leading to impaired protein kinase activity.
48	decreased acetylation; leading to enhanced protein kinase activity.
167	abrogates kinase activity.
175	constitutive kinase activity.
175	mimics phosphorylation, constitutive loss of kinase activity.
186	abrogates autophosphorylation; no effect on kinase activity, but impaired ctd phosphorylation.
186	mimics autophosphorylation; constitutive kinase activity, independently of calcium signaling.
347–357	loss of autophosphorylation and impaired interaction with hiv tat.
347–357	mimics autophosphorylation and promotes interaction with hiv tat.

Function

Pathways and Gene Ontology

Reactome pathways

34 pathways

ID	Pathway
R-HSA-112382	Formation of RNA Pol II elongation complex
R-HSA-167152	Formation of HIV elongation complex in the absence of HIV Tat
R-HSA-167200	Formation of HIV-1 elongation complex containing HIV-1 Tat
R-HSA-167238	Pausing and recovery of Tat-mediated HIV elongation
R-HSA-167243	Tat-mediated HIV elongation arrest and recovery
R-HSA-167246	Tat-mediated elongation of the HIV-1 transcript
R-HSA-167287	HIV elongation arrest and recovery
R-HSA-167290	Pausing and recovery of HIV elongation
R-HSA-176034	Interactions of Tat with host cellular proteins
R-HSA-2173796	SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription
R-HSA-674695	RNA Polymerase II Pre-transcription Events
R-HSA-6796648	TP53 Regulates Transcription of DNA Repair Genes
R-HSA-6807505	RNA polymerase II transcribes snRNA genes
R-HSA-75955	RNA Polymerase II Transcription Elongation
R-HSA-9018519	Estrogen-dependent gene expression
R-HSA-162582	Signal Transduction
R-HSA-162587	HIV Life Cycle
R-HSA-162599	Late Phase of HIV Life Cycle
R-HSA-162906	HIV Infection
R-HSA-162909	Host Interactions of HIV factors
R-HSA-1643685	Disease
R-HSA-167169	HIV Transcription Elongation
R-HSA-167172	Transcription of the HIV genome
R-HSA-170834	Signaling by TGF-beta Receptor Complex
R-HSA-212436	Generic Transcription Pathway
R-HSA-2173793	Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer
R-HSA-3700989	Transcriptional Regulation by TP53
R-HSA-5663205	Infectious disease
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)

MSigDB gene sets: 250 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, GOBP_DNA_TEMPLATED_DNA_REPLICATION_MAINTENANCE_OF_FIDELITY, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, PAX4_01, GOBP_RESPONSE_TO_PEPTIDE, GOBP_HOST_MEDIATED_ACTIVATION_OF_VIRAL_TRANSCRIPTION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_MODULATION_OF_PROCESS_OF_ANOTHER_ORGANISM, AP2_Q3, GOBP_HOST_MEDIATED_PERTURBATION_OF_VIRAL_PROCESS, GOBP_REGULATION_OF_DNA_REPAIR, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_LOCALIZATION, AACWWCAANK_UNKNOWN, REACTOME_HIV_INFECTION

GO Biological Process (22): DNA repair (GO:0006281), regulation of DNA repair (GO:0006282), transcription by RNA polymerase II (GO:0006366), transcription initiation at RNA polymerase II promoter (GO:0006367), transcription elongation by RNA polymerase II (GO:0006368), protein phosphorylation (GO:0006468), cell population proliferation (GO:0008283), replication fork processing (GO:0031297), regulation of mRNA 3’-end processing (GO:0031440), positive regulation of transcription elongation by RNA polymerase II (GO:0032968), host-mediated activation of viral transcription (GO:0043923), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of muscle cell differentiation (GO:0051147), nucleus localization (GO:0051647), regulation of cell cycle (GO:0051726), cellular response to cytokine stimulus (GO:0071345), negative regulation of protein localization to chromatin (GO:0120186), positive regulation of protein localization to chromatin (GO:0120187), transcription elongation-coupled chromatin remodeling (GO:0140673), DNA damage response (GO:0006974), negative regulation of transcription elongation by RNA polymerase II (GO:0034244), transcription pausing by RNA polymerase II (GO:0160239)

GO Molecular Function (20): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), transcription coactivator binding (GO:0001223), DNA binding (GO:0003677), chromatin binding (GO:0003682), transcription elongation factor activity (GO:0003711), 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), kinase activity (GO:0016301), protein kinase binding (GO:0019901), 7SK snRNA binding (GO:0097322), protein serine kinase activity (GO:0106310), histone H1-4S187 kinase activity (GO:0140191), nucleotide binding (GO:0000166), transcription cis-regulatory region binding (GO:0000976), protein binding (GO:0005515), transferase activity (GO:0016740), snRNA binding (GO:0017069)

GO Cellular Component (9): nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription elongation factor complex (GO:0008023), cyclin/CDK positive transcription elongation factor complex (GO:0008024), membrane (GO:0016020), PML body (GO:0016605), cytoplasmic ribonucleoprotein granule (GO:0036464), P-TEFb complex (GO:0070691), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Transcription of the HIV genome	5
RNA Polymerase II Transcription	3
HIV Infection	2
RNA Polymerase II Transcription Elongation	1
Tat-mediated elongation of the HIV-1 transcript	1
HIV Transcription Elongation	1
Host Interactions of HIV factors	1
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	1
Transcriptional Regulation by TP53	1
ESR-mediated signaling	1
HIV Life Cycle	1
Viral Infection Pathways	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transcription by RNA polymerase II	3
protein serine/threonine kinase activity	3
cellular anatomical structure	3
transcription elongation by RNA polymerase II	2
protein localization to chromatin	2
regulation of protein localization to chromatin	2
binding	2
protein kinase activity	2
DNA metabolic process	1
DNA damage response	1
DNA repair	1
regulation of DNA metabolic process	1
regulation of cellular response to stress	1
DNA-templated transcription	1
DNA-templated transcription initiation	1
DNA-templated transcription elongation	1
phosphorylation	1
protein modification process	1
cellular process	1
DNA-templated DNA replication maintenance of fidelity	1
mRNA 3’-end processing	1
regulation of mRNA processing	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
host-mediated perturbation of viral transcription	1
host-mediated activation of viral process	1
regulation of transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
muscle cell differentiation	1
regulation of cell differentiation	1
organelle localization	1
cell cycle	1
regulation of cellular process	1
response to cytokine	1
negative regulation of protein localization	1
positive regulation of protein localization	1
chromatin remodeling	1
cellular response to stress	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1

Protein interactions and networks

STRING

2982 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CDK9	CCNT1	O60563	999
CDK9	BRD4	O60885	999
CDK9	CCNT2	O60583	999
CDK9	HEXIM1	O94992	998
CDK9	CCNK	O75909	998
CDK9	CCNL2	Q96S94	994
CDK9	AFF4	Q9UHB7	989
CDK9	MEPCE	Q7L2J0	988
CDK9	AFF1	P51825	979
CDK9	LARP7	Q4G0J3	975
CDK9	MLLT1	Q03111	964
CDK9	ELL	P55199	950
CDK9	HTATSF1	O43719	915
CDK9	BRD2	P25440	898
CDK9	POLR2A	P24928	888

IntAct

245 interactions, top by confidence:

A	B	Type	Score
CDK9	CCNT1	psi-mi:“MI:0914”(association)	0.980
CCNT1	CDK9	psi-mi:“MI:0915”(physical association)	0.980
CDK9	CCNT1	psi-mi:“MI:0407”(direct interaction)	0.980
CCNT1	CDK9	psi-mi:“MI:0914”(association)	0.980
CCNT1	CDK9	psi-mi:“MI:0217”(phosphorylation reaction)	0.980
CDK9	CCNT1	psi-mi:“MI:0915”(physical association)	0.980
HEXIM1	CDK9	psi-mi:“MI:0914”(association)	0.940
CDK9	HEXIM1	psi-mi:“MI:0915”(physical association)	0.940
CDK9	LARP7	psi-mi:“MI:0915”(physical association)	0.930
HEXIM1	CCNT1	psi-mi:“MI:0914”(association)	0.930
CCNT1	HEXIM1	psi-mi:“MI:0914”(association)	0.930
LARP7	CDK9	psi-mi:“MI:0915”(physical association)	0.930
CDK9	CCNT2	psi-mi:“MI:0915”(physical association)	0.910
LARP7	CCNT1	psi-mi:“MI:0914”(association)	0.850

BioGRID (1273): MBP (Biochemical Activity), RB1 (Biochemical Activity), CDK9 (Reconstituted Complex), tat (Affinity Capture-Western), CCNT1 (Affinity Capture-Western), CDK9 (Co-fractionation), CDK9 (Co-fractionation), RNF20 (Co-fractionation), PAF1 (Co-fractionation), HIST2H2BE (Reconstituted Complex), CDK9 (Affinity Capture-MS), CDK9 (Affinity Capture-MS), LARP7 (Affinity Capture-MS), HSP90AA1 (Affinity Capture-MS), HSP90AB1 (Affinity Capture-MS)

ESM2 similar proteins: A0A194WDG1, A1CAF0, A1DES4, A2QN07, B0Y462, B0Y4X4, G4N374, O02812, O08911, O13352, O15264, O42376, O44408, O59854, O61443, O62618, P14681, P39745, P47811, P50750, P53778, P70618, Q00772, Q06060, Q0CIC7, Q16539, Q17446, Q1L5Z8, Q39026, Q3T0N5, Q40532, Q4WQR3, Q4WUN7, Q5J4W4, Q63538, Q750A9, Q84UI5, Q8MXI4, Q92398, Q95NE7

Diamond homologs: A0A509AH51, A0QNG1, A3B529, A3LUB9, A5D791, A6ZU08, A7E3S4, A8X0C4, A8XSC1, D0Z5N4, D4A7V9, E2QWQ2, O19004, P00531, P00532, P04049, P04627, P05625, P07527, P0CS76, P0CS77, P10398, P11345, P14056, P17157, P19525, P27636, P32490, P33279, P34331, P38990, P41676, P43637, P50750, P52304, P53351, P54666, Q03957, Q03963, Q04770

SIGNOR signaling

77 interactions.

A	Effect	B	Mechanism
CDK9	“up-regulates quantity by expression”	HES1	“transcriptional regulation”
CDK9	up-regulates	SUPT5H	phosphorylation
CDK9	“up-regulates activity”	TP53	phosphorylation
CDK9	unknown	TP53	phosphorylation
CDK9	down-regulates	SMAD1	phosphorylation
CDK9	“down-regulates quantity by destabilization”	SMAD1	phosphorylation
CDK9	“down-regulates activity”	SMAD3	phosphorylation
CDK9	down-regulates	SMAD3	phosphorylation
PPP1CC	up-regulates	CDK9	dephosphorylation
PPM1B	unknown	CDK9	dephosphorylation
4-(2-methyl-3-propan-2-yl-4-imidazolyl)-N-(4-methylsulfonylphenyl)-2-pyrimidinamine	down-regulates	CDK9	“chemical inhibition”
Dinaciclib	down-regulates	CDK9	“chemical inhibition”
alvocidib	down-regulates	CDK9	“chemical inhibition”
“alvocidib hydrochloride”	down-regulates	CDK9	“chemical inhibition”
CDK9	down-regulates	RCHY1	phosphorylation
CDK9	“up-regulates quantity by stabilization”	TP53	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 142 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
HIV elongation arrest and recovery	8	26.6×	3e-08
Pausing and recovery of HIV elongation	8	26.6×	3e-08
Formation of RNA Pol II elongation complex	13	24.2×	9e-13
RNA Polymerase II Transcription Elongation	13	24.2×	9e-13
Pausing and recovery of Tat-mediated HIV elongation	6	21.2×	1e-05
Tat-mediated HIV elongation arrest and recovery	6	21.2×	1e-05
RNA Polymerase II Pre-transcription Events	16	21.2×	1e-14
Formation of HIV elongation complex in the absence of HIV Tat	8	19.1×	4e-07

GO biological processes:

GO term	Partners	Fold	FDR
transcription elongation by RNA polymerase II	7	25.0×	4e-06
positive regulation of transcription elongation by RNA polymerase II	10	24.3×	7e-09
mRNA transcription by RNA polymerase II	6	16.0×	3e-04
transcription by RNA polymerase II	11	6.2×	3e-04
RNA splicing	8	5.7×	9e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	33
Likely benign	8
Benign	4

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
4682741	GRCh37/hg19 9q33.3-34.11(chr9:130075871-130589353)x1	Pathogenic

SpliceAI

925 predictions. Top by Δscore:

Variant	Effect	Δscore
9:127786236:TTCGG:T	donor_gain	1.0000
9:127786239:GG:G	donor_gain	1.0000
9:127786239:GGGTA:G	donor_loss	1.0000
9:127786240:GG:G	donor_gain	1.0000
9:127786240:GGTA:G	donor_loss	1.0000
9:127786241:G:C	donor_loss	1.0000
9:127786241:G:GG	donor_gain	1.0000
9:127786242:T:A	donor_loss	1.0000
9:127786692:C:CA	acceptor_gain	1.0000
9:127786696:T:A	acceptor_gain	1.0000
9:127786698:CAGGG:C	acceptor_gain	1.0000
9:127786699:A:AG	acceptor_gain	1.0000
9:127786699:A:T	acceptor_loss	1.0000
9:127786699:AG:A	acceptor_gain	1.0000
9:127786699:AGG:A	acceptor_gain	1.0000
9:127786699:AGGG:A	acceptor_gain	1.0000
9:127786700:G:A	acceptor_gain	1.0000
9:127786700:G:GA	acceptor_gain	1.0000
9:127786700:GGG:G	acceptor_gain	1.0000
9:127786700:GGGA:G	acceptor_gain	1.0000
9:127786700:GGGAG:G	acceptor_gain	1.0000
9:127786778:AGGGG:A	donor_gain	1.0000
9:127786779:GGGG:G	donor_gain	1.0000
9:127786779:GGGGG:G	donor_gain	1.0000
9:127786780:GGG:G	donor_gain	1.0000
9:127786780:GGGG:G	donor_gain	1.0000
9:127786781:GG:G	donor_gain	1.0000
9:127786781:GGG:G	donor_gain	1.0000
9:127786782:GG:G	donor_gain	1.0000
9:127786783:G:GG	donor_gain	1.0000

AlphaMissense

2468 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:127786224:G:C	G26R	1.000
9:127786224:G:T	G26C	1.000
9:127786225:G:A	G26D	1.000
9:127786225:G:T	G26V	1.000
9:127786230:G:A	G28S	1.000
9:127786230:G:C	G28R	1.000
9:127786230:G:T	G28C	1.000
9:127786231:G:A	G28D	1.000
9:127786231:G:C	G28A	1.000
9:127786231:G:T	G28V	1.000
9:127786234:C:T	T29I	1.000
9:127786236:T:A	F30I	1.000
9:127786236:T:C	F30L	1.000
9:127786236:T:G	F30V	1.000
9:127786237:T:C	F30S	1.000
9:127786237:T:G	F30C	1.000
9:127786238:C:A	F30L	1.000
9:127786238:C:G	F30L	1.000
9:127786239:G:A	G31R	1.000
9:127786239:G:C	G31R	1.000
9:127786239:G:T	G31W	1.000
9:127786240:G:A	G31E	1.000
9:127786240:G:T	G31V	1.000
9:127786705:G:A	V33M	1.000
9:127786705:G:C	V33L	1.000
9:127786705:G:T	V33L	1.000
9:127786706:T:A	V33E	1.000
9:127786706:T:C	V33A	1.000
9:127786745:C:A	A46D	1.000
9:127786748:T:C	L47P	1.000

dbSNP variants (sampled 300 via entrez): RS1000622607 (9:127784616 G>A,T), RS1000708079 (9:127787182 A>C,G), RS1000911478 (9:127784670 T>G), RS1000925389 (9:127784697 G>C), RS1001012071 (9:127788421 C>T), RS1001160087 (9:127788755 G>T), RS1001803652 (9:127786980 G>C), RS1001835047 (9:127787617 T>C), RS1002139320 (9:127787771 C>T), RS1002588988 (9:127791204 A>G), RS1002805270 (9:127785314 G>A), RS1003926040 (9:127785735 C>A,T), RS1004076414 (9:127784477 G>A), RS1004111784 (9:127790124 T>C), RS1004148674 (9:127790136 G>A)

Disease associations

OMIM: gene MIM:603251 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary breast carcinoma	Limited	Autosomal dominant

Mondo (1): hereditary breast carcinoma (MONDO:0016419)

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST005951_65	Body mass index	5.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C562840	Breast Cancer, Familial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (14): CHEMBL2111389 (PROTEIN COMPLEX), CHEMBL3038475 (PROTEIN COMPLEX), CHEMBL3116 (SINGLE PROTEIN), CHEMBL3559691 (PROTEIN FAMILY), CHEMBL4106184 (PROTEIN FAMILY), CHEMBL4523631 (PROTEIN COMPLEX), CHEMBL4523632 (PROTEIN COMPLEX), CHEMBL4523697 (PROTEIN-PROTEIN INTERACTION), CHEMBL5291961 (PROTEIN COMPLEX GROUP), CHEMBL6066141 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

62 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 99,208 (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
CHEMBL189963	PALBOCICLIB	4	13,102
CHEMBL3301610	ABEMACICLIB	4	7,045
CHEMBL3545110	RIBOCICLIB	4	8,018
CHEMBL3894860	TRILACICLIB	4	2,086
CHEMBL1078178	MOMELOTINIB	4	3,481
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL2035187	PACRITINIB	4	3,345
CHEMBL2103840	DINACICLIB	3	2,257
CHEMBL3904602	LEROCICLIB	3	1,012
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL2105728	CRENOLANIB	3	2,167
CHEMBL223360	LINIFANIB	3	3,925
CHEMBL300138	ENZASTAURIN	3	3,209
CHEMBL3137331	DEFACTINIB	3	1,229
CHEMBL3426621	RIPASUDIL	3	870
CHEMBL38380	FASUDIL	3	11,953
CHEMBL603469	LESTAURTINIB	3
CHEMBL14762	SELICICLIB	2	3,787
CHEMBL2347597	ASNUCICLIB	2	100
CHEMBL3115681	NARAZACICLIB	2	287
CHEMBL3545283	RIVICICLIB	2
CHEMBL3655762	CYC-065	2
CHEMBL3905910	VORUCICLIB	2
CHEMBL4067549	ULECACICLIB	2
CHEMBL4442620	RONICICLIB	2
CHEMBL4446357	EBVACICLIB	2
CHEMBL445813	AT-7519	2
CHEMBL4462530	ZEMIRCICLIB	2
CHEMBL5095094	CULMERCICLIB	2
CHEMBL5199065	ISTISOCICLIB	2

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1054774	CDK9, FPGS		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — CDK9 subfamily

Most potent curated ligand interactions (30 total), top 25:

Ligand	Action	Affinity	Parameter
NVP-2	Inhibition	9.3	pIC50
RGB-286638	Inhibition	9.0	pIC50
enitociclib	Inhibition	8.52	pIC50
zotiraciclib	Inhibition	8.52	pIC50
THAL-SNS-032	Inhibition	8.4	pIC50
zemirciclib	Inhibition	8.4	pIC50
asnuciclib	Inhibition	8.4	pKi
BMS-387032	Inhibition	8.4	pKi
dinaciclib	Inhibition	8.4	pIC50
istisociclib	Inhibition	8.22	pIC50
CDK9 inhibitor 1-7a-B1	Inhibition	8.19	pIC50
AT-7519	Inhibition	8.0	pIC50
riviciclib	Inhibition	7.7	pIC50
AZD5438	Inhibition	7.7	pIC50
voruciclib	Inhibition	7.66	pIC50
CDK inhibitor 4.35	Inhibition	7.6	pIC50
compound 89S [PMID: 19115845]	Inhibition	7.55	pIC50
kinase inhibitor 2 [PMID: 30199702]	Inhibition	7.31	pIC50
trilaciclib	Inhibition	7.3	pIC50
BS-194	Inhibition	7.05	pIC50
fadraciclib	Inhibition	7.0	pIC50
atuveciclib	Inhibition	6.42	pIC50
compound 18 [PMID: 20873740]	Inhibition	6.4	pIC50
seliciclib	Inhibition	6.1	pKi
samuraciclib	Inhibition	5.92	pIC50

Binding affinities (BindingDB)

2508 measured of 2700 human assays (2701 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
4-[[[6-[2-[(4-aminocyclohexyl)amino]-5-chloro-4-pyridinyl]-3-fluoro-2-pyridinyl]amino]methyl]oxane-4-carbonitrile	IC50	0.00015 nM	US-8778951: Heteroaryl compounds and their uses
4-[[[6-[5-chloro-2-[[4-(2-methoxyethylamino)cyclohexyl]amino]-4-pyridinyl]-3-fluoro-2-pyridinyl]amino]methyl]oxane-4-carbonitrile	IC50	0.00017 nM	US-8778951: Heteroaryl compounds and their uses
4-[[[6-[5-chloro-2-[[4-[[(2R)-1-methoxypropan-2-yl]amino]cyclohexyl]amino]-4-pyridinyl]-3-fluoro-2-pyridinyl]amino]methyl]oxane-4-carbonitrile	IC50	0.00023 nM	US-8778951: Heteroaryl compounds and their uses
4-[[[6-[5-chloro-2-[[4-(propylamino)cyclohexyl]amino]-4-pyridinyl]-3-fluoro-2-pyridinyl]amino]methyl]oxane-4-carbonitrile	IC50	0.00017 nM	US-8778951: Heteroaryl compounds and their uses
4-[[[6-[5-chloro-2-[(4-hydroxycyclohexyl)amino]-4-pyridinyl]-3-fluoro-2-pyridinyl]amino]methyl]oxane-4-carbonitrile	IC50	0.00016 nM	US-8778951: Heteroaryl compounds and their uses
4-[[[6-[5-chloro-2-[[4-[[(2R)-1-methoxypropan-2-yl]amino]cyclohexyl]amino]-4-pyridinyl]-2-pyridinyl]amino]methyl]oxane-4-carbonitrile	IC50	0.00017 nM	US-8778951: Heteroaryl compounds and their uses
4-[[[6-[5-chloro-2-[(4-hydroxycyclohexyl)amino]-4-pyridinyl]-2-pyridinyl]amino]methyl]oxane-4-carbonitrile	IC50	0.00024 nM	US-8778951: Heteroaryl compounds and their uses
4-[[[6-[5-chloro-2-[[4-[[(2R)-1-methoxypropan-2-yl]amino]cyclohexyl]amino]-4-pyridinyl]-2-pyridinyl]amino]methyl]oxane-4-carbonitrile	IC50	0.0003 nM	US-8778951: Heteroaryl compounds and their uses
4-N-[5-chloro-4-[5-fluoro-6-[(4-methyloxan-4-yl)methylamino]-2-pyridinyl]-2-pyridinyl]cyclohexane-1,4-diamine	IC50	0.0003 nM	US-8778951: Heteroaryl compounds and their uses
4-N-[5-chloro-4-[3,5-difluoro-6-(oxan-4-ylmethylamino)-2-pyridinyl]-2-pyridinyl]cyclohexane-1,4-diamine	IC50	0.00026 nM	US-8778951: Heteroaryl compounds and their uses
4-[[[6-[5-chloro-2-[[4-[(2-methyl-1,3-dioxolan-2-yl)amino]cyclohexyl]amino]-4-pyridinyl]-3-fluoro-2-pyridinyl]amino]methyl]oxane-4-carbonitrile	IC50	0.00027 nM	US-8778951: Heteroaryl compounds and their uses
4-[[[6-[5-chloro-2-[[4-(dipropylamino)cyclohexyl]amino]-4-pyridinyl]-3-fluoro-2-pyridinyl]amino]methyl]oxane-4-carbonitrile	IC50	0.00031 nM	US-8778951: Heteroaryl compounds and their uses
4-[[[6-[5-chloro-2-[[4-(ethylamino)cyclohexyl]amino]-4-pyridinyl]-2-pyridinyl]amino]methyl]oxane-4-carbonitrile	IC50	0.00028 nM	US-8778951: Heteroaryl compounds and their uses
4-[[[6-[5-chloro-2-[[4-(dimethylamino)cyclohexyl]amino]-4-pyridinyl]-2-pyridinyl]amino]methyl]oxane-4-carbonitrile	IC50	0.0003 nM	US-8778951: Heteroaryl compounds and their uses
4-[[[6-[5-chloro-2-[[4-[2-(trifluoromethoxy)ethylamino]cyclohexyl]amino]-4-pyridinyl]-2-pyridinyl]amino]methyl]oxane-4-carbonitrile	IC50	0.00036 nM	US-8778951: Heteroaryl compounds and their uses
4-[[[6-[5-chloro-2-[[4-(oxan-4-ylamino)cyclohexyl]amino]-4-pyridinyl]-2-pyridinyl]amino]methyl]oxane-4-carbonitrile	IC50	0.00043 nM	US-8778951: Heteroaryl compounds and their uses
4-N-[5-chloro-4-[5-fluoro-6-(oxan-4-ylmethylamino)-2-pyridinyl]-2-pyridinyl]-1-N-(2-methylsulfonylethyl)cyclohexane-1,4-diamine	IC50	0.00049 nM	US-8778951: Heteroaryl compounds and their uses
4-N-[5-chloro-4-[6-[(4-fluorooxan-4-yl)methylamino]-2-pyridinyl]-2-pyridinyl]-1-N-(2-methoxyethyl)cyclohexane-1,4-diamine	IC50	0.00063 nM	US-8778951: Heteroaryl compounds and their uses
1-N-[5-chloro-4-[6-[(4-methyl-1,1-dioxothian-4-yl)methylamino]-2-pyridinyl]-2-pyridinyl]-4-N-[(2R)-1-methoxypropan-2-yl]cyclohexane-1,4-diamine	IC50	0.0007 nM	US-8778951: Heteroaryl compounds and their uses
4-N-[5-chloro-4-[3-fluoro-6-(oxan-4-ylmethylamino)-2-pyridinyl]-2-pyridinyl]-1-N-(2-methoxyethyl)cyclohexane-1,4-diamine	IC50	0.001 nM	US-8778951: Heteroaryl compounds and their uses
4-N-[5-chloro-4-[6-[[(2R,6S)-2,6-dimethyloxan-4-yl]methylamino]-2-pyridinyl]-2-pyridinyl]cyclohexane-1,4-diamine	IC50	0.001 nM	US-8778951: Heteroaryl compounds and their uses
4-N-[4-[3-bromo-6-(oxan-4-ylmethylamino)-2-pyridinyl]-5-chloro-2-pyridinyl]cyclohexane-1,4-diamine	IC50	0.001 nM	US-8778951: Heteroaryl compounds and their uses
1-N-[5-chloro-4-[3-chloro-6-(oxan-4-ylmethylamino)-2-pyridinyl]-2-pyridinyl]-4-N-[(2R)-1-methoxypropan-2-yl]cyclohexane-1,4-diamine	IC50	0.001 nM	US-8778951: Heteroaryl compounds and their uses
1-N-[5-chloro-4-[3-fluoro-6-(oxan-4-ylmethylamino)-2-pyridinyl]-2-pyridinyl]-4-N-[(2R)-1-methoxypropan-2-yl]cyclohexane-1,4-diamine	IC50	0.001 nM	US-8778951: Heteroaryl compounds and their uses
1-N-[5-chloro-4-[5-fluoro-6-(oxan-4-ylmethylamino)-2-pyridinyl]-2-pyridinyl]-4-N-[(2R)-1-methoxypropan-2-yl]cyclohexane-1,4-diamine	IC50	0.001 nM	US-8778951: Heteroaryl compounds and their uses
4-[[5-chloro-4-[3-chloro-6-[(2,2-dimethyloxan-4-yl)methylamino]-2-pyridinyl]-2-pyridinyl]amino]cyclohexan-1-ol	IC50	0.001 nM	US-8778951: Heteroaryl compounds and their uses
(2S)-3-[[4-[[5-chloro-4-[3-chloro-6-[(2,2-dimethyloxan-4-yl)methylamino]-2-pyridinyl]-2-pyridinyl]amino]cyclohexyl]amino]-1,1,1-trifluoropropan-2-ol	IC50	0.001 nM	US-8778951: Heteroaryl compounds and their uses
(2R)-3-[[4-[[5-chloro-4-[3-chloro-6-[(2,2-dimethyloxan-4-yl)methylamino]-2-pyridinyl]-2-pyridinyl]amino]cyclohexyl]amino]-1,1,1-trifluoropropan-2-ol	IC50	0.001 nM	US-8778951: Heteroaryl compounds and their uses
4-N-[5-chloro-4-[3-chloro-6-(oxan-4-ylmethylamino)-2-pyridinyl]-2-pyridinyl]-1-N-[2-(trifluoromethoxy)ethyl]cyclohexane-1,4-diamine	IC50	0.001 nM	US-8778951: Heteroaryl compounds and their uses
1-N-[5-chloro-4-[6-[(4-methoxyoxan-4-yl)methylamino]-2-pyridinyl]-2-pyridinyl]-4-N-[(2R)-1-methoxypropan-2-yl]cyclohexane-1,4-diamine	IC50	0.001 nM	US-8778951: Heteroaryl compounds and their uses
1-N-[5-chloro-4-[6-(oxan-4-ylmethylamino)-5-(trifluoromethyl)-2-pyridinyl]-2-pyridinyl]-4-N-[(2R)-1-methoxypropan-2-yl]cyclohexane-1,4-diamine	IC50	0.001 nM	US-8778951: Heteroaryl compounds and their uses
4-N-[5-chloro-4-[6-[(4-methyloxan-4-yl)methylamino]-2-pyridinyl]-2-pyridinyl]cyclohexane-1,4-diamine	IC50	0.001 nM	US-8778951: Heteroaryl compounds and their uses
4-N-[5-chloro-4-[6-[(4-fluorooxan-4-yl)methylamino]-2-pyridinyl]-2-pyridinyl]cyclohexane-1,4-diamine	IC50	0.001 nM	US-8778951: Heteroaryl compounds and their uses
4-N-[5-chloro-4-[5-fluoro-6-(oxan-4-ylmethylamino)-2-pyridinyl]-2-pyridinyl]-1-N-(2-methoxyethyl)cyclohexane-1,4-diamine	IC50	0.001 nM	US-8778951: Heteroaryl compounds and their uses
4-N-[5-chloro-4-[3-chloro-6-(oxan-4-ylmethylamino)-2-pyridinyl]-2-pyridinyl]-1-N-[[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl]cyclohexane-1,4-diamine	IC50	0.001 nM	US-8778951: Heteroaryl compounds and their uses
1-N-[5-chloro-4-[3-chloro-6-[[(3S)-oxan-3-yl]methylamino]-2-pyridinyl]-2-pyridinyl]-4-N-[(2R)-1-methoxypropan-2-yl]cyclohexane-1,4-diamine	IC50	0.001 nM	US-8778951: Heteroaryl compounds and their uses
1-N-[5-chloro-4-[3-chloro-6-[[(3R)-oxan-3-yl]methylamino]-2-pyridinyl]-2-pyridinyl]-4-N-[(2R)-1-methoxypropan-2-yl]cyclohexane-1,4-diamine	IC50	0.001 nM	US-8778951: Heteroaryl compounds and their uses
1-N-[5-chloro-4-[6-[[(4S)-2,2-dimethyloxan-4-yl]methylamino]-2-pyridinyl]-2-pyridinyl]-4-N-[(2R)-1-methoxypropan-2-yl]cyclohexane-1,4-diamine	IC50	0.001 nM	US-8778951: Heteroaryl compounds and their uses
1-N-[5-chloro-4-[6-[(2,2-dimethyloxan-4-yl)methylamino]-2-pyridinyl]-2-pyridinyl]-4-N-[(2R)-1-methoxypropan-2-yl]cyclohexane-1,4-diamine	IC50	0.001 nM	US-8778951: Heteroaryl compounds and their uses
4-N-[5-chloro-4-[5-fluoro-6-(oxan-4-ylmethylamino)-2-pyridinyl]-2-pyridinyl]-1-N-[(1,1-dioxothian-4-yl)methyl]cyclohexane-1,4-diamine	IC50	0.001 nM	US-8778951: Heteroaryl compounds and their uses
4-N-[5-chloro-4-[5-fluoro-6-[(4-methyloxan-4-yl)methylamino]-2-pyridinyl]-2-pyridinyl]-1-N-(1,1-dioxothiolan-3-yl)cyclohexane-1,4-diamine	IC50	0.001 nM	US-8778951: Heteroaryl compounds and their uses
1-N-[5-chloro-4-[5-fluoro-6-[(4-methyloxan-4-yl)methylamino]-2-pyridinyl]-2-pyridinyl]-4-N-(2-methyl-1,3-dioxolan-2-yl)cyclohexane-1,4-diamine	IC50	0.001 nM	US-8778951: Heteroaryl compounds and their uses
4-N-[5-chloro-4-[5-fluoro-6-[(4-methyloxan-4-yl)methylamino]-2-pyridinyl]-2-pyridinyl]-1-N-(1,1-dioxothian-4-yl)cyclohexane-1,4-diamine	IC50	0.001 nM	US-8778951: Heteroaryl compounds and their uses
4-N-[5-chloro-4-[5-fluoro-6-[(4-methyloxan-4-yl)methylamino]-2-pyridinyl]-2-pyridinyl]-1-N-(1,1-dioxothietan-3-yl)cyclohexane-1,4-diamine	IC50	0.001 nM	US-8778951: Heteroaryl compounds and their uses
[4-[[[6-[5-chloro-2-[[4-[[(2R)-1-methoxypropan-2-yl]amino]cyclohexyl]amino]-4-pyridinyl]-2-pyridinyl]amino]methyl]oxan-4-yl]methanol	IC50	0.001 nM	US-8778951: Heteroaryl compounds and their uses
[4-[[[6-[5-chloro-2-[[4-(2-methoxyethylamino)cyclohexyl]amino]-4-pyridinyl]-2-pyridinyl]amino]methyl]oxan-4-yl]methanol	IC50	0.001 nM	US-8778951: Heteroaryl compounds and their uses
4-[[[6-[5-chloro-2-[[4-(diethylamino)cyclohexyl]amino]-4-pyridinyl]-2-pyridinyl]amino]methyl]oxane-4-carbonitrile	IC50	0.001 nM	US-8778951: Heteroaryl compounds and their uses
4-N-[5-chloro-4-[6-[[(2R,6S)-2,6-dimethyloxan-4-yl]methylamino]-2-pyridinyl]-2-pyridinyl]-1-N-(2-methoxyethyl)cyclohexane-1,4-diamine	IC50	0.002 nM	US-8778951: Heteroaryl compounds and their uses
(2S)-3-[[4-[[5-chloro-4-[3-chloro-6-(oxan-4-ylmethylamino)-2-pyridinyl]-2-pyridinyl]amino]cyclohexyl]amino]-1,1,1-trifluoropropan-2-ol	IC50	0.002 nM	US-8778951: Heteroaryl compounds and their uses
4-N-[4-[3-bromo-6-(oxan-4-ylmethylamino)-2-pyridinyl]-5-chloro-2-pyridinyl]-1-N-(2-methoxyethyl)cyclohexane-1,4-diamine	IC50	0.002 nM	US-8778951: Heteroaryl compounds and their uses

ChEMBL bioactivities

5314 potent at pChembl≥5 of 5373 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.82	IC50	0.015	nM	CHEMBL3694406
10.74	IC50	0.018	nM	CHEMBL3694400
10.72	IC50	0.019	nM	CHEMBL3694402
10.54	IC50	0.029	nM	CHEMBL3694407
10.41	IC50	0.039	nM	CHEMBL3694401
10.11	IC50	0.077	nM	CHEMBL6170958
10.05	Kd	0.0894	nM	ZEMIRCICLIB
9.94	IC50	0.116	nM	CHEMBL3694404
9.91	Kd	0.123	nM	CHEMBL4754081
9.76	IC50	0.173	nM	CHEMBL3694402
9.67	Kd	0.213	nM	CHEMBL5197170
9.53	Kd	0.295	nM	CHEMBL4754399
9.40	Ki	0.4	nM	CHEMBL3932121
9.40	IC50	0.4	nM	CHEMBL4217448
9.39	IC50	0.406	nM	CHEMBL5896735
9.38	IC50	0.416	nM	CHEMBL5833416
9.34	IC50	0.455	nM	CHEMBL5968336
9.32	IC50	0.477	nM	CHEMBL5882812
9.32	IC50	0.48	nM	CHEMBL6064411
9.31	IC50	0.489	nM	CHEMBL5915985
9.30	IC50	0.495	nM	CHEMBL4777844
9.30	IC50	0.498	nM	CHEMBL5807427
9.29	IC50	0.51	nM	CHEMBL3656841
9.28	IC50	0.528	nM	CHEMBL5869245
9.27	IC50	0.539	nM	CHEMBL5836297
9.22	IC50	0.6	nM	CHEMBL3969723
9.20	IC50	0.626	nM	VORUCICLIB
9.20	Ki	0.626	nM	VORUCICLIB
9.20	Ki	0.631	nM	CHEMBL422897
9.16	IC50	0.699	nM	CHEMBL6032739
9.16	IC50	0.694	nM	CHEMBL6038421
9.15	IC50	0.7	nM	CHEMBL4785212
9.15	Ki	0.7	nM	ALVOCIDIB
9.13	IC50	0.743	nM	CHEMBL5782315
9.12	IC50	0.76	nM	CHEMBL5752051
9.11	IC50	0.78	nM	CHEMBL5758584
9.10	IC50	0.794	nM	CHEMBL6003410
9.10	Ki	0.7943	nM	CHEMBL2006674
9.09	IC50	0.82	nM	CHEMBL5742354
9.08	IC50	0.837	nM	CHEMBL5860854
9.05	IC50	0.9	nM	CHEMBL5402757
9.04	IC50	0.92	nM	CHEMBL5947385
9.03	IC50	0.938	nM	CHEMBL5960234
9.02	IC50	0.961	nM	CHEMBL5739568
9.01	IC50	0.98	nM	CHEMBL5946521
9.01	IC50	0.979	nM	CHEMBL5871308
9.01	IC50	0.984	nM	CHEMBL5743027
9.00	IC50	1	nM	CHEMBL3957795
9.00	IC50	1	nM	CHEMBL3977324
9.00	IC50	1	nM	RGB-286638

PubChem BioAssay actives

2104 with measured affinity, of 5357 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
cis-(1S,3R)-3-acetamido-N-[4-(5,5-dimethyl-4,6-dihydropyrrolo[2,1-e]pyrazol-3-yl)-5-fluoro-2-pyridinyl]cyclohexane-1-carboxamide	1684241: Binding affinity to human CDK9/CyclinT assessed as equilibrium dissociation constant by surface plasmon resonance analysis	kd	0.0001	uM
cis-(1S,3R)-3-acetamido-N-[5-chloro-4-(5,5-dimethyl-4,6-dihydropyrrolo[2,1-e]pyrazol-3-yl)-2-pyridinyl]cyclohexane-1-carboxamide	1684241: Binding affinity to human CDK9/CyclinT assessed as equilibrium dissociation constant by surface plasmon resonance analysis	kd	0.0001	uM
5-[2-[1-(2-oxo-2-piperidin-1-ylethyl)piperidin-4-yl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-propan-2-ylpyridin-2-one	1847698: Binding affinity to CDK9 (unknown origin) assessed as dissociation constant by Surface Plasmon Resonance assay	kd	0.0002	uM
N,4-dimethyl-5-[2-(3-methylsulfonylanilino)pyrimidin-4-yl]-1,3-thiazol-2-amine	1799550: In Vitro Kinase Assay from Article 10.1016/j.chembiol.2010.07.016: “Discovery and characterization of 2-anilino-4- (thiazol-5-yl)pyrimidine transcriptional CDK inhibitors as anticancer agents.”	ki	0.0003	uM
cis-(1S,3R)-3-acetamido-N-[5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-2-pyridinyl]cyclohexane-1-carboxamide	1684241: Binding affinity to human CDK9/CyclinT assessed as equilibrium dissociation constant by surface plasmon resonance analysis	kd	0.0003	uM
3,4-dimethyl-5-[2-(4-piperazin-1-ylanilino)pyrimidin-4-yl]-1,3-thiazol-2-one	1317387: Inhibition of recombinant human His-tagged CDK9/cyclin T1 expressed in baculovirus infected sf9 cells using (biotinyl-Ahx-(Tyr-Ser-ProThr-Ser-Pro-Ser)4-NH2 as substrate after 45 mins by [gamma-32P]ATP based microbeta scintillation counting analysis	ki	0.0004	uM
4-[[4-(2,3-difluoro-6-methoxyphenyl)pyrimidin-2-yl]amino]-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide	1373254: Inhibition of N-terminal GST-HIS6 fusion protein tagged human full length CDK9 (M1 to F372 residues)/N-terminal GST-HIS6 fusion protein tagged human Cyclin-T1 (M1 to K726 residues) expressed in Sf9 cells at 10 uM using TAMRA-Rbtide substrate and ATP incubated for 1 hr by fluorescent polarization assay	ic50	0.0004	uM
4-N-[5-chloro-4-[6-[(3-fluorophenyl)methylamino]-2-pyridinyl]-2-pyridinyl]cyclohexane-1,4-diamine	2103751: Inhibition of CDK9 (unknown origin)	ic50	0.0004	uM
4-[[[6-[5-chloro-2-[[4-[[(2R)-1-methoxypropan-2-yl]amino]cyclohexyl]amino]-4-pyridinyl]-2-pyridinyl]amino]methyl]oxane-4-carbonitrile	1890144: Inhibition of CDK9 (unknown origin)	ic50	0.0005	uM
4-[[[6-[5-chloro-2-[[4-[[(2S)-1-methoxypropan-2-yl]amino]cyclohexyl]amino]-4-pyridinyl]-2-pyridinyl]amino]methyl]oxane-4-carbonitrile	1696617: Displacement of Alexa Fluor 647 ADP Tracer from His-tagged human CDK9/Cyclin T1 expressed in baculovirus expression system incubated for 1 hr by adapta assay	ic50	0.0005	uM
2-[2-chloro-4-(trifluoromethyl)phenyl]-5,7-dihydroxy-8-[(2R,3S)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]chromen-4-one	1868094: Inhibition of CDK9/Cyclin T2 (unknown origin)	ic50	0.0006	uM
7-[[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino]-4-morpholin-4-yl-3-propanoylchromen-2-one	1739162: Inhibition of CDK9/Cyclin T1 (unknown origin) preincubated for 20 mins followed by ATP addition and measured after 120 mins in presence of [33P-gamma] ATP by hotspot kinase assay	ic50	0.0007	uM
3-[[4-[4-methyl-2-(methylamino)-1,3-thiazol-5-yl]pyrimidin-2-yl]amino]benzenesulfonamide	1799550: In Vitro Kinase Assay from Article 10.1016/j.chembiol.2010.07.016: “Discovery and characterization of 2-anilino-4- (thiazol-5-yl)pyrimidine transcriptional CDK inhibitors as anticancer agents.”	ki	0.0008	uM
3,20-difluoro-N-(2-morpholin-4-ylethyl)-13,18-dioxa-5,7,25-triazatetracyclo[17.3.1.12,6.18,12]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene-11-carboxamide	2037436: Inhibition of CDK9/Cyclin-T1 (unknown origin) preincubated for 10 mins followed by substrate addition and measured after 60 mins in presence of ATP by ADP-Glo reagent based assay	ic50	0.0009	uM
1-[3-[4-[[4-(2-methoxyethyl)piperazin-1-yl]methyl]phenyl]-4-oxo-1H-indeno[2,1-d]pyrazol-5-yl]-3-morpholin-4-ylurea	1317393: Inhibition of CDK9/cyclin T1 (unknown origin)	ic50	0.0010	uM
N-ethyl-4-methyl-5-[2-(3-methylsulfonylanilino)pyrimidin-4-yl]-1,3-thiazol-2-amine	1799550: In Vitro Kinase Assay from Article 10.1016/j.chembiol.2010.07.016: “Discovery and characterization of 2-anilino-4- (thiazol-5-yl)pyrimidine transcriptional CDK inhibitors as anticancer agents.”	ki	0.0010	uM
5-fluoro-4-(4-fluoro-1-benzofuran-7-yl)-N-[3-methyl-5-(methylsulfonylmethyl)phenyl]pyrimidin-2-amine	1696593: Inhibition of His-tagged human CDK9/cyclin T1 expressed in insect cells using biotin Ttds-YISPLKSPYKISEG as substrate preincubated for 15 mins followed by ATP and substrate addition and measured after 25 mins by TR-FRET assay	ic50	0.0010	uM
4-[[[4-[5-chloro-2-[[4-(2-methoxyethylamino)cyclohexyl]amino]-4-pyridinyl]-1,3-thiazol-2-yl]amino]methyl]oxane-4-carbonitrile	1418190: Inhibition of recombinant full length His-tagged human CDK9/CyclinT1 expressed in baculovirus expression system	ic50	0.0010	uM
N-(3,4-dimethyl-1,2-oxazol-5-yl)-4-[[4-(2-fluoro-6-methoxyphenyl)pyrimidin-2-yl]amino]benzenesulfonamide	1373254: Inhibition of N-terminal GST-HIS6 fusion protein tagged human full length CDK9 (M1 to F372 residues)/N-terminal GST-HIS6 fusion protein tagged human Cyclin-T1 (M1 to K726 residues) expressed in Sf9 cells at 10 uM using TAMRA-Rbtide substrate and ATP incubated for 1 hr by fluorescent polarization assay	ic50	0.0010	uM
4-[[4-(2,3-difluoro-6-methoxyphenyl)pyrimidin-2-yl]amino]-N-(3,4-dimethyl-1,2-oxazol-5-yl)benzenesulfonamide	1373254: Inhibition of N-terminal GST-HIS6 fusion protein tagged human full length CDK9 (M1 to F372 residues)/N-terminal GST-HIS6 fusion protein tagged human Cyclin-T1 (M1 to K726 residues) expressed in Sf9 cells at 10 uM using TAMRA-Rbtide substrate and ATP incubated for 1 hr by fluorescent polarization assay	ic50	0.0010	uM
(16E)-14-methyl-20-oxa-5,7,14,27-tetrazatetracyclo[19.3.1.12,6.18,12]heptacosa-1(25),2(27),3,5,8,10,12(26),16,21,23-decaene	1424950: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0010	uM
N-[5-[(5-tert-butyl-1,3-oxazol-2-yl)methylsulfanyl]-1,3-thiazol-2-yl]piperidine-4-carboxamide	2195218: Inhibition of CDK9/Cyclin T1 (unknown origin) using ULight MBP peptide as substrate in presence of ATP incubated for 1 hr by FRET based LANCE Ultra KinaSelect screen assay	ic50	0.0010	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	1781579: Inhibition of CDK9 (unknown origin) expressed in Sf9 insect cells using biotinylated peptide derived Histone H1 as substrate incubated for 1 hr in presence of [gamma33P]ATP by liquid scintillation counter method	ic50	0.0010	uM
4-[4-fluoro-2-[(2-fluoro-4-pyridinyl)methoxy]phenyl]-N-[3-(methylsulfonylmethyl)phenyl]-1,3,5-triazin-2-amine	1317375: Inhibition of human recombinant full length His-tagged CDK9/cyclin T1 expressed in insect cells using biotin-Ttds-YISPLKSPYKISEG as substrate preincubated for 15 mins measured after 25 mins by TR-FRET assay	ic50	0.0010	uM
(3R)-N-[5-chloro-4-[5-fluoro-6-(oxan-4-ylmethylamino)-2-pyridinyl]-2-pyridinyl]piperidine-3-carboxamide	1317371: Inhibition of CDK9/cyclin T1 (unknown origin) using cdk7tide peptide as substrate	ic50	0.0010	uM
4-ethyl-6-[[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino]-8-(morpholin-4-ylmethyl)-1,4-benzoxazin-3-one	1883436: Inhibition of CDK9/Cyclin T1 (unknown origin) preincubated for 10 mins followed by ATP and CTD3 addition and measured after 30 mins by mobility shift assay	ic50	0.0011	uM
N-[2-(dimethylamino)ethyl]-3,20-difluoro-13,18-dioxa-5,7,25-triazatetracyclo[17.3.1.12,6.18,12]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaene-11-carboxamide	2037436: Inhibition of CDK9/Cyclin-T1 (unknown origin) preincubated for 10 mins followed by substrate addition and measured after 60 mins in presence of ATP by ADP-Glo reagent based assay	ic50	0.0011	uM
3,21-difluoro-N-(2-morpholin-4-ylethyl)-13,19-dioxa-5,7,26-triazatetracyclo[18.3.1.12,6.18,12]hexacosa-1(24),2(26),3,5,8(25),9,11,20,22-nonaene-11-carboxamide	2037436: Inhibition of CDK9/Cyclin-T1 (unknown origin) preincubated for 10 mins followed by substrate addition and measured after 60 mins in presence of ATP by ADP-Glo reagent based assay	ic50	0.0011	uM
3-acetyl-4-(4-ethylpiperazin-1-yl)-7-[[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino]chromen-2-one	1739162: Inhibition of CDK9/Cyclin T1 (unknown origin) preincubated for 20 mins followed by ATP addition and measured after 120 mins in presence of [33P-gamma] ATP by hotspot kinase assay	ic50	0.0012	uM
4-N-[2-(dimethylamino)ethyl]-7-N-[4-(2-methyl-3-propan-2-ylindazol-5-yl)pyrimidin-2-yl]quinazoline-4,7-diamine	1771099: Inhibition of human CDK9/cyclin-T1 using KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC as substrate incubated for 2 hrs by [gamma-33P]-ATP assay	ic50	0.0012	uM
3-[4-[4-(5-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3,6-dihydro-2H-pyridin-1-yl]propane-1,2-diol	1696620: Inhibition of CDK9 (unknown origin) using Ulight-labeled substrate by TR-FRET LANCE method	ic50	0.0012	uM
[2-[[4-(3-propan-2-ylbenzotriazol-5-yl)-2-pyridinyl]amino]-4-pyridinyl]-pyrrolidin-1-ylmethanone	2081988: Inhibition of CDK9/Cyclin T1 (unknown origin) using PDKtide substrate incubated for 60 mins by ADP-Glo kinase assay	ic50	0.0013	uM
5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-[4-(methylsulfonylmethyl)-2-pyridinyl]pyridin-2-amine	1814978: Inhibition of CDK9 (unknown origin) assessed as dissociation constant by DiscoveryX assay	kd	0.0013	uM
N-[(E)-(6-bromoimidazo[1,2-a]pyridin-3-yl)methylideneamino]-N,2-dimethyl-5-nitrobenzenesulfonamide	1245692: Inhibition of recombinant human CDK9/cyclin-T1 using H-YSPTSPSYSPTSPSYSPTSPS-KKKK-OH as substrate after 90 mins by luminescence assay	ic50	0.0014	uM
3-acetyl-7-[[4-(2-methyl-3-propan-2-ylindazol-5-yl)pyrimidin-2-yl]amino]-4-morpholin-4-ylchromen-2-one	1771099: Inhibition of human CDK9/cyclin-T1 using KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC as substrate incubated for 2 hrs by [gamma-33P]-ATP assay	ic50	0.0014	uM
3-acetyl-7-[[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino]-4-(4-methylpiperazin-1-yl)chromen-2-one	1739162: Inhibition of CDK9/Cyclin T1 (unknown origin) preincubated for 20 mins followed by ATP addition and measured after 120 mins in presence of [33P-gamma] ATP by hotspot kinase assay	ic50	0.0015	uM
7-[[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino]-4-morpholin-4-ylchromen-2-one	1739162: Inhibition of CDK9/Cyclin T1 (unknown origin) preincubated for 20 mins followed by ATP addition and measured after 120 mins in presence of [33P-gamma] ATP by hotspot kinase assay	ic50	0.0016	uM
3-acetyl-4-(1,4-diazepan-1-yl)-7-[[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino]chromen-2-one	1739162: Inhibition of CDK9/Cyclin T1 (unknown origin) preincubated for 20 mins followed by ATP addition and measured after 120 mins in presence of [33P-gamma] ATP by hotspot kinase assay	ic50	0.0016	uM
4-ethyl-6-[[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino]-8-[[4-(oxetan-3-yl)piperazin-1-yl]methyl]-1,4-benzoxazin-3-one	1883436: Inhibition of CDK9/Cyclin T1 (unknown origin) preincubated for 10 mins followed by ATP and CTD3 addition and measured after 30 mins by mobility shift assay	ic50	0.0016	uM
[2-[2-chloro-4-(trifluoromethyl)phenyl]-5-hydroxy-8-[(2R,3S)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]-4-oxochromen-7-yl] dihydrogen phosphate	1696650: Inhibition of N-terminal His6-tagged thrombin cleavage site-fused human CDK9 (M1 to F372 residues)/cyclin-T1 (M1 to K726 residues) expressed in baculovirus infected Sf9 insect cells in presence of gamma-33P-ATP by filter binding assay	ki	0.0017	uM
3-acetyl-7-[[5-chloro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino]-4-(4-methylpiperazin-1-yl)chromen-2-one	1739162: Inhibition of CDK9/Cyclin T1 (unknown origin) preincubated for 20 mins followed by ATP addition and measured after 120 mins in presence of [33P-gamma] ATP by hotspot kinase assay	ic50	0.0017	uM
N-[5-[(5-tert-butyl-1,3-oxazol-2-yl)methylsulfanyl]-1,3-thiazol-2-yl]-1-[4-(prop-2-enoylamino)benzoyl]piperidine-3-carboxamide	1652518: Inhibition of recombinant human full-length His-tagged CDK9/Cyclin T1 expressed in baculovirus infection system using Cdk7/9tide as substrate measured after 1 hr in presence of Alexa Fluor 647 ADP Tracer-based Adapta assay	ic50	0.0018	uM
3-[[4-(3,4-dimethyl-2-oxo-1,3-thiazol-5-yl)pyrimidin-2-yl]amino]benzonitrile	1799550: In Vitro Kinase Assay from Article 10.1016/j.chembiol.2010.07.016: “Discovery and characterization of 2-anilino-4- (thiazol-5-yl)pyrimidine transcriptional CDK inhibitors as anticancer agents.”	ki	0.0019	uM
2-[(E)-2-(2,6-dichlorophenyl)ethenyl]-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]chromen-4-one	1479297: Inhibition of CDK9/cyclin T1 (unknown origin) using YSPTSPSYSPTSPSYSPTSPKKK as substrate after 30 mins in presence of [33P]-gamma-ATP by filter binding assay	ic50	0.0019	uM
4-(4-methylpiperazin-1-yl)-N-[4-(2-methyl-3-propan-2-ylindazol-5-yl)pyrimidin-2-yl]quinolin-7-amine	1771099: Inhibition of human CDK9/cyclin-T1 using KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC as substrate incubated for 2 hrs by [gamma-33P]-ATP assay	ic50	0.0019	uM
4-ethyl-6-[[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino]-8-[[(3R)-3-methylmorpholin-4-yl]methyl]-1,4-benzoxazin-3-one	1883436: Inhibition of CDK9/Cyclin T1 (unknown origin) preincubated for 10 mins followed by ATP and CTD3 addition and measured after 30 mins by mobility shift assay	ic50	0.0019	uM
N-[4-[11-[(3R)-3-aminopyrrolidin-1-yl]-7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-2-yl]-2-pyridinyl]cyclopropanecarboxamide;hydrochloride	2000055: Inhibition of CDK9/CyclinT1 (unknown origin) by ADP-Glo kinase assay	ic50	0.0019	uM
N-[4-[12-[(3S)-3-aminopyrrolidin-1-yl]-6,7,8,9,10,11-hexahydrocycloocta[b]quinolin-2-yl]-2-pyridinyl]cyclopropanecarboxamide;hydrochloride	2000055: Inhibition of CDK9/CyclinT1 (unknown origin) by ADP-Glo kinase assay	ic50	0.0019	uM
4-(4-methylpiperazin-1-yl)-N-[4-(2-methyl-3-propan-2-ylindazol-5-yl)pyrimidin-2-yl]quinazolin-7-amine	2103762: Inhibition of CDK9 (unknown origin) by ADP-Glo kinase assay	ic50	0.0019	uM
4-[2-[[4-(3-propan-2-ylbenzotriazol-5-yl)-2-pyridinyl]amino]pyridine-4-carbonyl]piperazin-2-one	2081988: Inhibition of CDK9/Cyclin T1 (unknown origin) using PDKtide substrate incubated for 60 mins by ADP-Glo kinase assay	ic50	0.0019	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases reaction, decreases expression, affects binding, decreases activity, affects cotreatment	3
(+)-JQ1 compound	affects localization, increases expression, affects binding, affects cotreatment, decreases reaction (+2 more)	3
dinaciclib	decreases activity	2
Tretinoin	increases expression	2
Valproic Acid	increases expression, increases methylation	2
Aflatoxin B1	decreases methylation	2
Cadmium Chloride	decreases expression, increases expression	2
GSK-J4	decreases expression	1
FR900359	increases phosphorylation	1
TAK-243	increases sumoylation	1
cinobufagin	increases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	decreases expression	1
arsenite	increases reaction, affects binding	1
afimoxifene	decreases response to substance	1
tetrabromobisphenol A	decreases expression	1
perfluorooctanoic acid	decreases expression	1
4-hydroxy-2-nonenal	decreases expression	1
aflatoxin B2	increases methylation	1
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	decreases expression	1
vanadium pentoxide	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
alvocidib	affects binding, decreases activity	1
wogonin	decreases activity	1
2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone	affects binding, decreases reaction	1
olomoucine II	decreases activity	1
N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide	decreases activity	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
AG-012986	decreases activity	1

ChEMBL screening assays

1449 unique, capped per target: 1435 binding, 9 functional, 4 admet, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1002045	Binding	Inhibition of CDK9/cyclinT by IMAP florescence polarization assay	A diaminocyclohexyl analog of SNS-032 with improved permeability and bioavailability properties. — Bioorg Med Chem Lett
CHEMBL4814491	ADMET	Inhibition of human recombinant CDK9/CyclinT expressed in baculovirus infected Sf9 cells using YSPTSPSYSPTSPSYSPTSPSKKK as substrate in presence of ATP measured after 30 mins by ADP-Glo assay	In vitro identification of imidazo[1,2-a]pyrazine-based antileishmanial agents and evaluation of L. major casein kinase 1 inhibition. — Eur J Med Chem
CHEMBL1963831	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: CDK9	PubChem BioAssay data set

Cellosaurus cell lines

4 cell lines: 3 embryonic stem cell, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A0M2	SEES3-1V human CDK9, clone1	Embryonic stem cell	Male
CVCL_A0M3	SEES3-1V human CDK9, clone2	Embryonic stem cell	Male
CVCL_A0M4	SEES3-1V human CDK9, clone3	Embryonic stem cell	Male
CVCL_D9ZW	Ubigene HeLa CDK9 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00040222	Not specified	COMPLETED	Clinical, Genetic, Behavioral, Laboratory and Epidemiologic Characterization of Individuals and Families at High Risk of Breast/Ovarian Cancer
NCT02557776	Not specified	COMPLETED	Written Genetic Counseling and Mutation Analysis of BRCA1 and BRCA2 to Patients With Breast Cancer
NCT03495544	Not specified	UNKNOWN	Study Estimating Association Between Germline Mutations and PD-L1 Expression in Breast Cancer
NCT03959267	Not specified	COMPLETED	Testing a Culturally Adapted Telephone Genetic Counseling Intervention
NCT04058418	Not specified	COMPLETED	Specialist Recommendation on FBC (Familial Breast Cancer) Chemoprevention Prescribing
NCT04125914	Not specified	ACTIVE_NOT_RECRUITING	Weight Management and Health Behavior Intervention in Lowering Cancer Risk for BRCA Positive and Lynch Syndrome Families
NCT04169542	Not specified	RECRUITING	Impact of COVID-19 Pandemic on Out-of-Pocket Costs, Lost Wages, and Unemployment in Patients With Breast Cancer Undergoing Breast Surgery
NCT04197856	Not specified	ACTIVE_NOT_RECRUITING	Direct Information to At-risk Relatives
NCT07292246	Not specified	RECRUITING	A Prospective CohorT Study of HandX - Assisted ENdoscopic MAstectomy: Feasibility and Safety (ATHENA I Study)
NCT07307664	Not specified	RECRUITING	Increasing Germline Genetic Testing for Patients With Cancer