CLK1

Summary

CLK1 (CDC like kinase 1, HGNC:2068) is a protein-coding gene on chromosome 2q33.1, encoding Dual specificity protein kinase CLK1 (P49759). Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates.

This gene encodes a member of the CDC2-like (or LAMMER) family of dual specificity protein kinases. In the nucleus, the encoded protein phosphorylates serine/arginine-rich proteins involved in pre-mRNA processing, releasing them into the nucleoplasm. The choice of splice sites during pre-mRNA processing may be regulated by the concentration of transacting factors, including serine/arginine rich proteins. Therefore, the encoded protein may play an indirect role in governing splice site selection. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 1195 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 99 total
• Druggable target: yes — 67 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004071

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2068
Approved symbol	CLK1
Name	CDC like kinase 1
Location	2q33.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000013441
Ensembl biotype	protein_coding
OMIM	601951
Entrez	1195

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 8 retained_intron, 7 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000321356, ENST00000409403, ENST00000409769, ENST00000432425, ENST00000434813, ENST00000461326, ENST00000461981, ENST00000464454, ENST00000472679, ENST00000473565, ENST00000481641, ENST00000482590, ENST00000492793, ENST00000496205, ENST00000851932, ENST00000851933, ENST00000851934, ENST00000948484

RefSeq mRNA: 2 — MANE Select: NM_004071 NM_001162407, NM_004071

CCDS: CCDS2331, CCDS54427

Canonical transcript exons

ENST00000321356 — 13 exons

Exon	Start	End
ENSE00001823451	200853009	200853449
ENSE00001865543	200864564	200864658
ENSE00002408030	200861238	200861466
ENSE00002472362	200860125	200860215
ENSE00003489950	200857973	200858089
ENSE00003505207	200856891	200856985
ENSE00003518423	200855004	200855086
ENSE00003530091	200857718	200857884
ENSE00003532245	200859680	200859746
ENSE00003571615	200854616	200854695
ENSE00003577713	200861702	200861862
ENSE00003607651	200856682	200856811
ENSE00003681068	200853903	200853993

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.30.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 73.1459 / max 1636.3120, expressed in 1820 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
33185	57.1615	1814
33186	15.3631	1732
33182	0.3821	135
33183	0.1326	39
33177	0.1066	36

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.30	gold quality
right uterine tube	UBERON:0001302	99.28	gold quality
right ovary	UBERON:0002118	99.28	gold quality
left ovary	UBERON:0002119	99.26	gold quality
tibial nerve	UBERON:0001323	99.25	gold quality
adenohypophysis	UBERON:0002196	99.24	gold quality
left lobe of thyroid gland	UBERON:0001120	99.17	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.17	gold quality
endocervix	UBERON:0000458	99.16	gold quality
mucosa of stomach	UBERON:0001199	99.16	gold quality
right lung	UBERON:0002167	99.15	gold quality
ventricular zone	UBERON:0003053	99.15	gold quality
lower esophagus mucosa	UBERON:0035834	99.15	gold quality
right lobe of thyroid gland	UBERON:0001119	99.03	gold quality
body of pancreas	UBERON:0001150	99.03	gold quality
ganglionic eminence	UBERON:0004023	99.03	gold quality
cerebellar hemisphere	UBERON:0002245	99.01	gold quality
body of uterus	UBERON:0009853	99.00	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.99	gold quality
cerebellar cortex	UBERON:0002129	98.96	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.96	gold quality
metanephros cortex	UBERON:0010533	98.94	gold quality
lower esophagus	UBERON:0013473	98.93	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.93	gold quality
calcaneal tendon	UBERON:0003701	98.89	gold quality
ectocervix	UBERON:0012249	98.89	gold quality
popliteal artery	UBERON:0002250	98.88	gold quality
tibial artery	UBERON:0007610	98.88	gold quality
skin of abdomen	UBERON:0001416	98.86	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.86	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-86618	yes	524.58
E-HCAD-1	yes	5.86
E-ENAD-20	no	297.38
E-HCAD-4	no	30.28
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI2

miRNA regulators (miRDB)

23 targeting CLK1, 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-4282	99.99	75.36	6408
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-12129	99.72	67.45	1311
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-302B-5P	99.50	69.49	1857
HSA-MIR-302D-5P	99.50	69.34	1863
HSA-MIR-12132	99.47	68.90	1341
HSA-MIR-6853-3P	99.36	70.79	1558
HSA-MIR-4427	99.34	70.33	1854
HSA-MIR-8065	99.19	70.38	1289
HSA-MIR-622	98.99	66.48	1050
HSA-MIR-522-3P	98.91	68.56	1817
HSA-MIR-224-3P	98.91	68.42	1815
HSA-MIR-942-3P	98.81	69.04	876
HSA-MIR-4463	98.56	66.05	1071
HSA-MIR-4718	98.55	68.61	814
HSA-MIR-4275	97.96	68.42	1549
HSA-MIR-3156-5P	96.93	67.36	800
HSA-MIR-5579-5P	96.32	68.54	730
HSA-MIR-151A-3P	95.52	65.29	516

Literature-anchored findings (GeneRIF, showing 23)

• Clk/Sty is found in the nucleus of several different cell types and is a factor directly involved in splicing control (PMID:12773558)
• ASF/SF2 is phosphorylated by SRPK1 and Clk/Sty (PMID:16223727)
• five genes (TNFSF10/TRAIL, IL1RN, IFI27, GZMB, and CCR5) were upregulated and three genes (CLK1, TNFAIP3 and BTG1) were downregulated in at least three out of four subpopulations during acute GVHD. (PMID:18814951)
• Cdc2-like kinases and DNA topoisomerase I regulate alternative splicing of tissue factor in human endothelial cells. (PMID:19168442)
• CLK1 Increases While CLK2 Decreases HIV-1 Gene Expression. (PMID:21682887)
• The data establish a new view of SRSF1 protein regulation in which SRPK1 and CLK1 partition activities based on Ser-Pro versus Arg-Ser placement rather than on N- and C-terminal preferences along the RS domain. (PMID:23707382)
• findings suggest that CLK1-dependent hyperphosphorylation is the result of a general mechanism in which the N-terminus acts as a bridge connecting the kinase domain and the RS domain of the SR protein. (PMID:24869919)
• Data suggest that proline phosphorylation by CLK1/CDC-like kinase 1 (but not by SRPK1/serine/arginine-rich splicing factor kinase 1) regulates conformation and alternative splicing function of SFRS1 (serine/arginine-rich splicing factor 1). (PMID:25529026)
• Nuclear CLK-1 mediates a retrograde signalling pathway that is conserved from Caenorhabditis elegans to humans and is responsive to mitochondrial reactive oxygen species, thus acting as a barometer of oxidative metabolism. (PMID:25961505)
• removal of the N-terminus or dilution of CLK1 induces monomer formation and reverses this specificity. CLK1 self-association also occurs in the nucleus (PMID:26443864)
• These results thus reveal a large program of CLK1-regulated periodic alternative splicing intimately associated with cell cycle control. (PMID:27015110)
• Clk1, Clk2 and Clk4 prevent chromatin breakage by regulating the Aurora B-dependent abscission checkpoint. (PMID:27126587)
• SRPK1 interacts with an RS-like domain in the N terminus of CLK1 to facilitate the release of phosphorylated SR proteins, which then promotes efficient splice-site recognition and subsequent spliceosome assembly. (PMID:27397683)
• Global CLK-dependent exon recognition and conjoined gene formation revealed with a novel small molecule inhibitor has been described. (PMID:28232751)
• that mitochondrial Clk1 regulated chemoresistance in glioma cells through AMPK/mTOR/HIF-1alpha mediated glycolysis pathway (PMID:28581641)
• We now show that the ability of SRPK1 to mobilize SRSF1 from speckles to the nucleoplasm is dependent on active CLK1. Diffusion from speckles is promoted by the formation of an SRPK1-CLK1 complex that facilitates dissociation of SRSF1 from CLK1 and enhances the phosphorylation of several serine-proline dipeptides in this SR protein (PMID:29335301)
• Data suggest that CLK1 activity in both transformed and normal cells is carefully regulated via CLK1 alternative splicing through both exon 4 skipping and intron 4 retention. CLK1 autoregulates by favoring the expression of truncated isoforms, CLK1T1 and CLKT2 in environmental stress. (PMID:29802995)
• found that CLK1 amplifies its presence in the nucleus by forming a stable complex with the Ser-Arg protein substrate (PMID:31064840)
• LncRNA-dependent nuclear stress bodies promote intron retention through SR protein phosphorylation. (PMID:31782550)
• Phosphoproteomic analysis identifies CLK1 as a novel therapeutic target in gastric cancer. (PMID:32333232)
• A conserved sequence motif bridges two protein kinases for enhanced phosphorylation and nuclear function of a splicing factor. (PMID:32359191)
• CLK1 reorganizes the splicing factor U1-70K for early spliceosomal protein assembly. (PMID:33811140)
• Functions of SRPK, CLK and DYRK kinases in stem cells, development, and human developmental disorders. (PMID:37607329)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	clk4b	ENSDARG00000005908
mus_musculus	Clk1	ENSMUSG00000026034
rattus_norvegicus	Clk1	ENSRNOG00000025768
drosophila_melanogaster	mnb	FBGN0259168
caenorhabditis_elegans		WBGENE00003149
caenorhabditis_elegans		WBGENE00013727
caenorhabditis_elegans		WBGENE00185089

Paralogs (12): DYRK4 (ENSG00000010219), HIPK2 (ENSG00000064393), DYRK1B (ENSG00000105204), HIPK3 (ENSG00000110422), CLK4 (ENSG00000113240), DYRK2 (ENSG00000127334), DYRK3 (ENSG00000143479), DYRK1A (ENSG00000157540), HIPK4 (ENSG00000160396), HIPK1 (ENSG00000163349), CLK2 (ENSG00000176444), CLK3 (ENSG00000179335)

Protein

Protein identifiers

Dual specificity protein kinase CLK1 — P49759 (reviewed: P49759)

Alternative names: CDC-like kinase 1

All UniProt accessions (3): P49759, B8ZZR0, F8WBF5

UniProt curated annotations — full annotation on UniProt →

Function. Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex and may be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing. Phosphorylates: SRSF1, SRSF3 and PTPN1. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells.

Subunit / interactions. Interacts with PPIG and UBL5.

Subcellular location. Nucleus.

Tissue specificity. Endothelial cells.

Post-translational modifications. Autophosphorylates on all three types of residues.

Activity regulation. Regulates splicing of its own pre-mRNA according to its kinase activity; increased expression of the catalytically active form influences splicing to generate the catalytically inactive splicing variant lacking the kinase domain. Leucettine L41 inhibits its kinase activity and affects the regulation of alternative splicing mediated by phosphorylation of SR proteins.

Miscellaneous. Lacks the kinase domain. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

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

Isoforms (3)

UniProt ID	Names	Canonical?
P49759-1	1, Long	yes
P49759-2	2, Short
P49759-3	3

RefSeq proteins (2): NP_001155879, NP_004062* (*=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
IPR051175	CLK_kinases	Family

Pfam: PF00069

Enzyme classification (BRENDA):

• EC 2.7.12.1 — dual-specificity kinase (BRENDA: 51 organisms, 125 substrates, 188 inhibitors, 14 Km, 10 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.019–0.1185	7
HISTONE H1	0.006–0.012	5

Catalyzed reactions (Rhea), 3 shown:

• L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) (RHEA:10596)
• 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 (57 total): helix 16, strand 12, sequence variant 6, turn 5, compositionally biased region 4, modified residue 3, splice variant 3, binding site 2, region of interest 2, chain 1, domain 1, sequence conflict 1, active site 1

Structure

Experimental structures (PDB)

38 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6FT8	X-RAY DIFFRACTION	1.45
6I5H	X-RAY DIFFRACTION	1.49
6I5I	X-RAY DIFFRACTION	1.6
6Z50	X-RAY DIFFRACTION	1.6
6QTY	X-RAY DIFFRACTION	1.65
7O9Y	X-RAY DIFFRACTION	1.66
1Z57	X-RAY DIFFRACTION	1.7
6ZLN	X-RAY DIFFRACTION	1.7
6R8J	X-RAY DIFFRACTION	1.75
2VAG	X-RAY DIFFRACTION	1.8
6TW2	X-RAY DIFFRACTION	1.8
8UWN	X-RAY DIFFRACTION	1.8
7OA0	X-RAY DIFFRACTION	1.81
6R3D	X-RAY DIFFRACTION	1.85
6FT9	X-RAY DIFFRACTION	1.87
5X8I	X-RAY DIFFRACTION	1.9
7OPG	X-RAY DIFFRACTION	1.93
6YTG	X-RAY DIFFRACTION	1.95
6YTD	X-RAY DIFFRACTION	2
6G33	X-RAY DIFFRACTION	2.05
6R6X	X-RAY DIFFRACTION	2.05
6Z4Z	X-RAY DIFFRACTION	2.07
6RAA	X-RAY DIFFRACTION	2.1
6R6E	X-RAY DIFFRACTION	2.25
6Q8K	X-RAY DIFFRACTION	2.29
6I5K	X-RAY DIFFRACTION	2.3
6YTA	X-RAY DIFFRACTION	2.3
6YTE	X-RAY DIFFRACTION	2.3
6FYO	X-RAY DIFFRACTION	2.32
6YTI	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49759-F1	78.56	0.65

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): 288 (proton acceptor)

Ligand- & substrate-binding residues (2): 191; 167–175

Post-translational modifications (3): 61, 138, 140

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 231 (showing top): ENK_UV_RESPONSE_KERATINOCYTE_UP, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, MARTINEZ_RB1_TARGETS_UP, GOBP_RNA_SPLICING, WINTER_HYPOXIA_METAGENE, DEBIASI_APOPTOSIS_BY_REOVIRUS_INFECTION_UP, NAKAMURA_TUMOR_ZONE_PERIPHERAL_VS_CENTRAL_DN, TCCAGAT_MIR5165P, NOJIMA_SFRP2_TARGETS_UP, IGLESIAS_E2F_TARGETS_UP, PRAMOONJAGO_SOX4_TARGETS_UP, GTATGAT_MIR154_MIR487, RIGGINS_TAMOXIFEN_RESISTANCE_DN, MCCLUNG_COCAIN_REWARD_4WK, PODAR_RESPONSE_TO_ADAPHOSTIN_UP

GO Biological Process (2): regulation of RNA splicing (GO:0043484), protein phosphorylation (GO:0006468)

GO Molecular Function (11): protein serine/threonine kinase activity (GO:0004674), protein serine/threonine/tyrosine kinase activity (GO:0004712), protein tyrosine kinase activity (GO:0004713), non-membrane spanning protein tyrosine kinase activity (GO:0004715), ATP binding (GO:0005524), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (1): nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein kinase activity	4
RNA splicing	1
regulation of gene expression	1
regulation of primary metabolic process	1
phosphorylation	1
protein modification process	1
protein tyrosine kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

934 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLK1	DDX23	Q9BUQ8	830
CLK1	SRSF2	Q01130	815
CLK1	CYCS	P00001	809
CLK1	NKTR	P30414	762
CLK1	SRSF1	Q07955	591
CLK1	PPIG	Q13427	539
CLK1	NOLC1	Q14978	526
CLK1	SRSF6	Q13247	521
CLK1	PIN4	Q9Y237	497
CLK1	EIF4EBP2	Q13542	492
CLK1	UBL5	Q9BZL1	490
CLK1	CRY2	Q49AN0	484
CLK1	CRY1	Q16526	483
CLK1	SRSF3	P23152	475
CLK1	EIF4E	P06730	458

IntAct

63 interactions, top by confidence:

A	B	Type	Score
YWHAG	CLK1	psi-mi:“MI:0915”(physical association)	0.670
CLK1	PDE9A	psi-mi:“MI:0915”(physical association)	0.560
CLK1	KRTAP10-7	psi-mi:“MI:0915”(physical association)	0.560
PDE9A	CLK1	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-7	CLK1	psi-mi:“MI:0915”(physical association)	0.560
SYMPK	CPSF4	psi-mi:“MI:0914”(association)	0.530
ZC3H18	AQR	psi-mi:“MI:0914”(association)	0.530
N	RBM47	psi-mi:“MI:0914”(association)	0.530
RPL13	RRP8	psi-mi:“MI:0914”(association)	0.530
SRSF3	CASC3	psi-mi:“MI:0914”(association)	0.530
CLK1	MFHAS1	psi-mi:“MI:0407”(direct interaction)	0.440
CLK1	SRPK2	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
SRPK1	CLK1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
CLK1	PTPN1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
CLK1	PSEN2	psi-mi:“MI:0915”(physical association)	0.400
espY1	CLK1	psi-mi:“MI:0915”(physical association)	0.370
CLK1	espY1	psi-mi:“MI:0915”(physical association)	0.370
	CLK1	psi-mi:“MI:0915”(physical association)	0.370
CLK1	PIAS4	psi-mi:“MI:0915”(physical association)	0.370
CLK1	PRMT5	psi-mi:“MI:0915”(physical association)	0.370
AKAP5	MRPL43	psi-mi:“MI:0914”(association)	0.350
Kif1b	NCOA4	psi-mi:“MI:0914”(association)	0.350
Rab11fip1	ZKSCAN1	psi-mi:“MI:0914”(association)	0.350
KLC1	RBFOX2	psi-mi:“MI:0914”(association)	0.350
PPP4R3A	COG4	psi-mi:“MI:0914”(association)	0.350
Insr	IGF1R	psi-mi:“MI:0914”(association)	0.350
	TBKBP1	psi-mi:“MI:0914”(association)	0.350

BioGRID (260): PDE9A (Two-hybrid), KRTAP10-7 (Two-hybrid), CLK1 (Affinity Capture-MS), PRPF4B (Reconstituted Complex), ABCA13 (Biochemical Activity), ACOX2 (Biochemical Activity), ANKFY1 (Biochemical Activity), ARHGEF12 (Biochemical Activity), ARPC4 (Biochemical Activity), ASL (Biochemical Activity), ASXL3 (Biochemical Activity), ATP10A (Biochemical Activity), ATP4A (Biochemical Activity), C1orf94 (Biochemical Activity), C3orf67 (Biochemical Activity)

ESM2 similar proteins: A1CL96, A1D624, A2X0M1, A2Y4B6, O35491, O35492, O35493, O35831, O35832, O44514, P22518, P46551, P49759, P49760, P49761, P51566, P51567, P83099, Q00536, Q00537, Q04735, Q09437, Q0CQK1, Q0E459, Q11179, Q23357, Q3SX21, Q4FCZ5, Q4I5U9, Q4WYR6, Q53N72, Q5BAE1, Q5SN53, Q5VP69, Q5Z9J0, Q5ZCI1, Q5ZIU3, Q63117, Q63686, Q67C40

Diamond homologs: A4L9P5, A8WJR8, A8X4H1, A8X5H5, B3WFY8, G5EDB2, O14132, O23145, O43781, O55076, O76039, O88850, O88904, P14680, P18265, P18431, P20911, P22518, P24941, P43288, P43289, P48963, P49657, P49759, P49840, P50613, P51136, P51567, P51568, P51952, P83102, Q00526, Q03147, Q04859, Q07538, Q08DZ2, Q09690, Q09815, Q0IJ08, Q10156

SIGNOR signaling

14 interactions.

A	Effect	B	Mechanism
CLK1	down-regulates	ABL1	phosphorylation
CLK1	“up-regulates activity”	SRSF1	phosphorylation
CLK1	“up-regulates activity”	PTPN1	phosphorylation
CLK1	“up-regulates activity”	RBM17	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 65 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	8	63.4×	3e-11
RNA Polymerase II Transcription Termination	9	41.2×	4e-11
mRNA 3’-end processing	9	36.9×	9e-11
mRNA Splicing	11	25.2×	3e-11
Transport of Mature mRNA derived from an Intron-Containing Transcript	7	22.2×	7e-07
Processing of Capped Intron-Containing Pre-mRNA	12	20.5×	3e-11
mRNA Polyadenylation	11	20.1×	2e-10
mRNA Splicing - Major Pathway	12	13.7×	1e-09

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of mRNA splicing, via spliceosome	5	68.4×	7e-07
regulation of alternative mRNA splicing, via spliceosome	9	39.2×	4e-10
RNA splicing	10	15.8×	1e-07
mRNA processing	10	14.1×	2e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	67
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1440 predictions. Top by Δscore:

Variant	Effect	Δscore
2:200853445:AATTC:A	acceptor_gain	1.0000
2:200853446:ATTC:A	acceptor_gain	1.0000
2:200853447:TTC:T	acceptor_gain	1.0000
2:200853448:TC:T	acceptor_gain	1.0000
2:200853449:CC:C	acceptor_gain	1.0000
2:200853450:C:CC	acceptor_gain	1.0000
2:200853450:CTGGA:C	acceptor_loss	1.0000
2:200854611:CGTA:C	donor_loss	1.0000
2:200854612:GTAC:G	donor_loss	1.0000
2:200854613:TACC:T	donor_loss	1.0000
2:200854615:C:A	donor_loss	1.0000
2:200854694:GTCT:G	acceptor_loss	1.0000
2:200854696:C:CC	acceptor_gain	1.0000
2:200855002:A:AC	donor_gain	1.0000
2:200855003:C:CC	donor_gain	1.0000
2:200856678:TCAC:T	donor_loss	1.0000
2:200856679:CACCT:C	donor_loss	1.0000
2:200856680:A:AC	donor_gain	1.0000
2:200856680:AC:A	donor_gain	1.0000
2:200856681:C:CT	donor_gain	1.0000
2:200856681:CC:C	donor_gain	1.0000
2:200856681:CCT:C	donor_gain	1.0000
2:200856681:CCTA:C	donor_gain	1.0000
2:200856681:CCTAA:C	donor_gain	1.0000
2:200856807:CGTTT:C	acceptor_gain	1.0000
2:200856808:GTTT:G	acceptor_gain	1.0000
2:200856809:TTT:T	acceptor_gain	1.0000
2:200856810:TT:T	acceptor_gain	1.0000
2:200856811:TCTG:T	acceptor_loss	1.0000
2:200856812:C:CC	acceptor_gain	1.0000

AlphaMissense

3273 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:200853366:T:A	R465S	1.000
2:200853366:T:G	R465S	1.000
2:200853367:C:G	R465T	1.000
2:200854673:A:G	L388S	1.000
2:200855021:C:A	G375W	1.000
2:200855047:C:T	G366E	1.000
2:200855052:G:C	S364R	1.000
2:200855052:G:T	S364R	1.000
2:200855054:T:G	S364R	1.000
2:200855055:C:A	W363C	1.000
2:200855055:C:G	W363C	1.000
2:200855057:A:G	W363R	1.000
2:200855057:A:T	W363R	1.000
2:200855078:A:G	W356R	1.000
2:200855078:A:T	W356R	1.000
2:200856696:G:T	P348H	1.000
2:200856701:T:A	R346S	1.000
2:200856701:T:G	R346S	1.000
2:200856702:C:G	R346T	1.000
2:200856706:A:G	Y345H	1.000
2:200856714:G:A	T342I	1.000
2:200856764:G:C	D325E	1.000
2:200856764:G:T	D325E	1.000
2:200856765:T:A	D325V	1.000
2:200856765:T:C	D325G	1.000
2:200856765:T:G	D325A	1.000
2:200856766:C:G	D325H	1.000
2:200856939:G:C	N293K	1.000
2:200856939:G:T	N293K	1.000
2:200856940:T:A	N293I	1.000

dbSNP variants (sampled 300 via entrez): RS1000347458 (2:200863027 G>A,C), RS1000462798 (2:200866474 T>A,G), RS1000666823 (2:200863945 T>C), RS1000769825 (2:200863461 G>T), RS1001124061 (2:200862162 T>C), RS1001319291 (2:200856514 G>A), RS1001329272 (2:200862469 A>G), RS1001371069 (2:200856278 G>T), RS1001838671 (2:200863399 A>C), RS1002016392 (2:200866013 G>A,C), RS1002397209 (2:200863179 G>A), RS1002637170 (2:200865815 T>A), RS1002755164 (2:200865570 GTTTT>G,GTT,GTTT,GTTTTT), RS1002999359 (2:200855574 G>A), RS1003026344 (2:200855285 G>A)

Disease associations

OMIM: gene MIM:601951 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST003008_2	Triptolide cytotoxicity	6.000000e-07
GCST003842_21	Breast cancer (estrogen-receptor negative)	1.000000e-06
GCST003845_22	Breast cancer	7.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006952	cytotoxicity measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL4106176 (PROTEIN FAMILY), CHEMBL4224 (SINGLE PROTEIN), CHEMBL5291951 (PROTEIN FAMILY), CHEMBL6066547 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

67 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 428,777 (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
CHEMBL1078178	MOMELOTINIB	4	3,481
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL1738797	ALECTINIB	4	6,731
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL189963	PALBOCICLIB	4	13,102
CHEMBL1946170	REGORAFENIB	4	12,678
CHEMBL2035187	PACRITINIB	4	3,345
CHEMBL2105759	BARICITINIB	4	6,741
CHEMBL2325741	CAPIVASERTIB	4	2,157
CHEMBL2403108	CERITINIB	4	8,551
CHEMBL255863	NILOTINIB	4	38,627
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3301610	ABEMACICLIB	4	7,045
CHEMBL3348923	TOVORAFENIB	4	834
CHEMBL3545311	BRIGATINIB	4	5,634
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL941	IMATINIB	4	111,611
CHEMBL140	CURCUMIN	3
CHEMBL2103840	DINACICLIB	3
CHEMBL223360	LINIFANIB	3
CHEMBL297453	EPIGALOCATECHIN GALLATE	3
CHEMBL300138	ENZASTAURIN	3
CHEMBL3137331	DEFACTINIB	3
CHEMBL3545308	ROCILETINIB	3
CHEMBL38380	FASUDIL	3
CHEMBL428690	ALVOCIDIB	3
CHEMBL4297639	LORECIVIVINT	3

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — CLK family

Most potent curated ligand interactions (9 total), top 9:

Ligand	Action	Affinity	Parameter
leucettine L41	Inhibition	10.82	pIC50
compound 17 [PMID: 23642479]	Inhibition	8.7	pIC50
KH-CB19	Inhibition	7.71	pIC50
Cdc2-like kinase inhibitor	Inhibition	7.7	pIC50
compound 3b [PMID: 23454515]	Inhibition	7.21	pIC50
ML315	Inhibition	7.17	pIC50
compound 2 [PMID: 22560567]	Inhibition	6.68	pIC50
MW01	Inhibition	6.6	pIC50
MW05	Inhibition	5.65	pIC50

Binding affinities (BindingDB)

54 measured of 58 human assays (58 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(10S,17E)-8,10,12,16-tetramethyl- 2,8,10,11,12,13-hexahydro-3,5- etheno[1,2]oxazolo[5,4-f]dipyrazolo[3,4- j:4’,3’-n][1,4]oxazacyclopentadecine	IC50	0.11 nM	US-20250353864: INDAZOLE CONTAINING MACROCYCLES AND THEIR USE
(10S,17E)-8,10,12,16-tetramethyl- 2,8,10,11,12,13-hexahydro-3,5- ethenodipyrazolo[3,4-j:4’,3’- n][1,2]thiazolo[3,4- f][1,4]oxazacyclopentadecine	IC50	0.14 nM	US-20250353864: INDAZOLE CONTAINING MACROCYCLES AND THEIR USE
(10S,13S,17E)-8,10,12,13,14,16- hexamethyl-2,10,11,12,13,14-hexahydro- 8H-3,5-ethenotripyrazolo[3,4-f:3’,4’- j:4″,3″-n][1,4]oxazacyclopentadecine	IC50	0.21 nM	US-20250353864: INDAZOLE CONTAINING MACROCYCLES AND THEIR USE
1-[(17E)-8,15,16-trimethyl- 2,8,10,11,13,15-hexahydro-12H-3,5- ethenotripyrazolo[3,4-f:3’,4’-j:4″,3″- n][1,4]oxazacyclopentadecin-12- yl]ethan-1-one	IC50	0.24 nM	US-20250353864: INDAZOLE CONTAINING MACROCYCLES AND THEIR USE
(17E)-8,14,16-trimethyl-2,8,9,11,12,14- hexahydro-3,5- etheno[1,4]dioxacyclopentadecino[11,10- c:15,14-c’:6,7-c″]tripyrazole	IC50	0.34 nM	US-20250353864: INDAZOLE CONTAINING MACROCYCLES AND THEIR USE
(10S,17E)-14-(2-hydroxyethyl)-8,10,12- trimethyl-2,10,11,12,13,14-hexahydro- 8H-3,5-ethenotripyrazolo[3,4-f:3’,4’- j:4″,3″-n][1,4]oxazacyclopentadecine-16- carbonitrile	IC50	0.59 nM	US-20250353864: INDAZOLE CONTAINING MACROCYCLES AND THEIR USE
2-[(10S,17E)-16-(ethylamino)-8,10,12- trimethyl-2,8,10,11,12,13-hexahydro- 14H-3,5-ethenotripyrazolo[3,4-f:3’,4’- j:4″,3″-n][1,4]oxazacyclopentadecin-14- yl]ethan-1-ol	IC50	0.64 nM	US-20250353864: INDAZOLE CONTAINING MACROCYCLES AND THEIR USE
2-{(10S,13S,17E)-8,10,12,13- tetramethyl-16-[(propan-2-yl)oxy]- 2,8,10,11,12,13-hexahydro-14H-3,5- ethenotripyrazolo[3,4-f:3’,4’-j:4″,3″- n][1,4]oxazacyclopentadecin-14- yl}ethan-1-ol	IC50	0.69 nM	US-20250353864: INDAZOLE CONTAINING MACROCYCLES AND THEIR USE
2-[(10S,17E)-16-ethoxy-6-ethynyl- 8,10,12-trimethyl-2,8,10,11,12,13- hexahydro-14H-3,5- ethenotripyrazolo[3,4-f:3’,4’-j:4″,3″- n][1,4]oxazacyclopentadecin-14- yl]ethan-1-ol	IC50	1.01 nM	US-20250353864: INDAZOLE CONTAINING MACROCYCLES AND THEIR USE
(2S)-1-{(10S,17E)-12-ethyl-19-fluoro- 8,10-dimethyl-16-[(propan-2-yl)oxy]- 2,8,10,11,12,13-hexahydro-14H-3,5- ethenotripyrazolo[3,4-f:3’,4’-j:4″,3″- n][1,4]oxazacyclopentadecin-14- yl}propan-2-ol	IC50	1.2 nM	US-20250353864: INDAZOLE CONTAINING MACROCYCLES AND THEIR USE
1-[(17E)-16-ethoxy-8,15-dimethyl- 2,8,10,11,13,15-hexahydro-12H-3,5- ethenotripyrazolo[3,4-f:3’,4’-j:4″,3″- n][1,4]oxazacyclopentadecin-12- yl]ethan-1-one	IC50	1.27 nM	US-20250353864: INDAZOLE CONTAINING MACROCYCLES AND THEIR USE
Staurosporine	KD	1.7 nM
QL-X-138	IC50	7 nM	US-10000483: Bone marrow on X chromosome kinase (BMX) inhibitors and uses thereof
4-[[4-cyclopentyloxy-5-[4-(methylcarbamoyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methoxy-N-methylbenzamide	IC50	34 nM	US-9623028: Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof
4-[(4-methoxy-5-pyridin-4-yl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]-N,N,3-trimethylbenzamide	IC50	41.5 nM	US-9623028: Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof
3A5	IC50	51 nM
4-[[4-(4-hydroxy-4-methylcyclohexyl)oxy-5-[4-(methylcarbamoyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methoxy-N-(1-methylazetidin-3-yl)benzamide	IC50	59.3 nM	US-9623028: Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof
(10S,17E)-16-ethoxy-12-ethyl-14-(2- hydroxyethyl)-8,10-dimethyl- 2,10,11,12,13,14-hexahydro-8H-3,5- ethenotripyrazolo[3,4-f:3’,4’-j:4″,3″- n][1,4]oxazacyclopentadecine-6- carbonitrile	IC50	69.4 nM	US-20250353864: INDAZOLE CONTAINING MACROCYCLES AND THEIR USE
4-[[5-(4-hydroxyphenyl)-4-(oxan-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methoxy-N-methylbenzamide	IC50	82.4 nM	US-9623028: Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof
3-cyano-N-methyl-4-[[5-(2-methyl-1,3-benzoxazol-6-yl)-4-(oxan-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]benzamide	IC50	82.8 nM	US-9623028: Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof
3-chloro-N-methyl-4-[[5-[4-(methylcarbamoyl)phenyl]-4-(oxan-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]benzamide	IC50	84.6 nM	US-9623028: Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof
3-chloro-N-methyl-4-[[5-(1-methylpyrazol-4-yl)-4-(oxan-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]benzamide	IC50	97.8 nM	US-9623028: Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof
3-methoxy-N-methyl-4-[[5-(2-methyl-1,3-benzoxazol-6-yl)-4-(oxan-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]benzamide	IC50	124 nM	US-9623028: Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof
3-chloro-N-methyl-4-[[5-(2-methyl-1,3-benzoxazol-6-yl)-4-[(3S)-oxolan-3-yl]oxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]benzamide	IC50	130 nM	US-9623028: Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof
N-methyl-4-[[5-(2-methyl-1,3-benzoxazol-6-yl)-4-(oxan-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-(trifluoromethyl)benzamide	IC50	172 nM	US-9623028: Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof
PKC-412	KD	190 nM
N,3-dimethyl-4-[[5-(2-methyl-1,3-benzoxazol-6-yl)-4-(oxan-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]benzamide	IC50	220 nM	US-9623028: Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof
4-[[4-(cyclopentylamino)-5-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methoxy-N-methylbenzamide	IC50	225 nM	US-9623028: Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof
3-chloro-N-methyl-4-[[5-(2-methyl-1,3-benzoxazol-6-yl)-4-(oxan-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]benzamide	IC50	226 nM	US-9623028: Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof
4-[[4-cyclopentyloxy-5-(2-methyl-1,3-benzoxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-2-fluoro-5-methoxy-N-methylbenzamide	IC50	237 nM	US-9623028: Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof
(2R)-2-[[6-(benzylamino)-9-isopropyl-purin-2-yl]amino]butan-1-ol	KD	260 nM
5F4	IC50	273 nM
5E4	IC50	277 nM
4-[[4-cyclopentyloxy-5-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-N-methyl-3-propan-2-ylbenzamide	IC50	299 nM	US-9623028: Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof
NR9	IC50	390 nM
1-[4-(3-amino-1H-indazol-4-yl)phenyl]-3-(2-fluoro-5-methyl-phenyl)urea	KD	450 nM
4-[[4-cyclopentyloxy-5-(2-methyl-1,3-benzoxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-N-(2-hydroxyethyl)-3-methoxybenzamide	IC50	501 nM	US-9623028: Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof
3-chloro-4-[[4-cyclopentyloxy-5-(2-methyl-1,3-benzoxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-N-methylbenzamide	IC50	505 nM	US-9623028: Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof
(3Z)-4-amino-5-fluoro-3-[5-(4-methylpiperazino)-1,3-dihydrobenzimidazol-2-ylidene]carbostyril	KD	520 nM
4-[[4-cyclobutyloxy-5-(2-methyl-1,3-benzoxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methoxy-N-(oxetan-3-yl)benzamide	IC50	526 nM	US-9623028: Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof
SCH772984	IC50	580 nM
(18S)-18-[(dimethylamino)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.1^{7,14}.0^{2,6}.0^{8,13}.0^{22,27}]nonacosa-1(28),2(6),7(29),8(13),9,11,22(27),23,25-nonaene-3,5-dione	KD	700 nM
4-[[4-cyclopentyloxy-5-(2-methyl-1,3-benzoxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methoxy-N-methylbenzamide	IC50	728 nM	US-9623028: Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof
4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinazolin-4-yl]-N-(4-propan-2-yloxyphenyl)piperazine-1-carboxamide	KD	740 nM
4-[(4-methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl]benzamide	KD	1000 nM
1-[4-[(4-ethyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]urea	KD	1400 nM
4-[[4-cyclopentyloxy-5-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methoxy-N-methylbenzamide	IC50	1440 nM	US-9623028: Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof
BMS-387072	KD	1800 nM
3-(4-morpholin-4-ylpyrido[2,3]furo[2,4-b]pyrimidin-2-yl)phenol	KD	2400 nM
5-[(Z)-(5-fluoranyl-2-oxidanylidene-1H-indol-3-ylidene)methyl]-2,4-dimethyl-N-[(2S)-3-morpholin-4-yl-2-oxidanyl-propyl]-1H-pyrrole-3-carboxamide	KD	2600 nM

ChEMBL bioactivities

1168 potent at pChembl≥5 of 1230 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.74	Kd	0.018	nM	CIRTUVIVINT
10.25	Kd	0.056	nM	CHEMBL393525
9.65	Kd	0.224	nM	CHEMBL5653589
9.64	Kd	0.228	nM	CHEMBL4441878
9.60	Kd	0.254	nM	CHEMBL4647659
9.50	ED50	0.313	nM	CHEMBL5653589
9.49	Kd	0.326	nM	CHEMBL5070553
9.41	Kd	0.388	nM	5-(6-BENZOTHIAZOLYLMETHYLENE)-3,5-DIHYDRO-2-(((1S)-1-(METHOXYMETHYL)-3-METHYLBUTYL)AMINO)-4H-IMIDAZOL-4-ONE, (5Z)-
9.40	Kd	0.395	nM	CHEMBL5081787
9.27	Kd	0.54	nM	SILMITASERTIB
9.24	Kd	0.58	nM	CHEMBL5279705
9.21	Kd	0.62	nM	CHEMBL5285332
9.17	IC50	0.67	nM	T3-CLK
9.07	Kd	0.851	nM	ABEMACICLIB
9.01	Kd	0.968	nM	CHEMBL5289681
9.00	IC50	1	nM	CHEMBL5428750
8.96	IC50	1.1	nM	CHEMBL5200367
8.96	IC50	1.1	nM	CHEMBL5283453
8.96	IC50	1.1	nM	CHEMBL5286791
8.89	Kd	1.273	nM	CHEMBL1232500
8.88	Kd	1.306	nM	CHEMBL4873449
8.86	Kd	1.387	nM	CHEMBL5273528
8.85	IC50	1.4	nM	CHEMBL5424488
8.85	Kd	1.4	nM	CHEMBL379218
8.79	Kd	1.626	nM	CHEMBL3298236
8.78	IC50	1.68	nM	CHEMBL5574295
8.77	IC50	1.7	nM	CHEMBL5424844
8.76	Kd	1.754	nM	CHEMBL5283849
8.70	IC50	2	nM	CHEMBL2392364
8.70	Kd	2	nM	RGB-286638
8.70	IC50	2	nM	CHEMBL4083249
8.59	Kd	2.6	nM	CHEMBL5093650
8.58	Kd	2.607	nM	CHEMBL5091238
8.56	AC50	2.72	nM	CHEMBL1329627
8.55	Kd	2.789	nM	CHEMBL1236620
8.50	AC50	3.14	nM	CHEMBL1702086
8.46	IC50	3.49	nM	T3-CLK
8.44	AC50	3.61	nM	CHEMBL1354134
8.43	IC50	3.7	nM	CHEMBL5411169
8.40	IC50	4	nM	CHEMBL4853178
8.40	IC50	4	nM	CHEMBL5205505
8.40	IC50	4	nM	T3-CLK
8.40	IC50	4	nM	CHEMBL5408531
8.40	IC50	4	nM	CHEMBL5428651
8.40	IC50	4	nM	5-(6-BENZOTHIAZOLYLMETHYLENE)-3,5-DIHYDRO-2-(((1S)-1-(METHOXYMETHYL)-3-METHYLBUTYL)AMINO)-4H-IMIDAZOL-4-ONE, (5Z)-
8.34	IC50	4.6	nM	CHEMBL6143642
8.32	Kd	4.8	nM	CHEMBL4797564
8.32	IC50	4.8	nM	CHEMBL4797564
8.31	AC50	4.9	nM	CHEMBL1899256
8.30	IC50	5	nM	CHEMBL4089159

PubChem BioAssay actives

1012 with measured affinity, of 2495 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
2-(4-methylpiperazin-1-yl)-N-[6-(1-methylpyrazol-4-yl)isoquinolin-3-yl]pyridine-4-carboxamide	1947697: Binding affinity to human CLK1 assessed as equilibrium dissociation constant measured upto 240 min by TR-FRET assay	kd	<0.0001	uM
N-[(E)-(6-bromoimidazo[1,2-a]pyridin-3-yl)methylideneamino]-N,2-dimethyl-5-nitrobenzenesulfonamide	1947697: Binding affinity to human CLK1 assessed as equilibrium dissociation constant measured upto 240 min by TR-FRET assay	kd	0.0001	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148083: Binding affinity to human CLK1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0002	uM
4-(2-methyl-3-propan-2-ylimidazo[4,5-b]pyridin-5-yl)pyridine-2,6-diamine	1947697: Binding affinity to human CLK1 assessed as equilibrium dissociation constant measured upto 240 min by TR-FRET assay	kd	0.0002	uM
4-[2-methyl-3-(2,2,2-trifluoroethyl)imidazo[4,5-b]pyridin-5-yl]pyridine-2,6-diamine	1947697: Binding affinity to human CLK1 assessed as equilibrium dissociation constant measured upto 240 min by TR-FRET assay	kd	0.0003	uM
(3R)-1-[3-[[3-amino-6-(2-fluoro-5-propan-2-yloxyphenyl)pyrazine-2-carbonyl]amino]-4-pyridinyl]piperidine-3-carboxylic acid	1947697: Binding affinity to human CLK1 assessed as equilibrium dissociation constant measured upto 240 min by TR-FRET assay	kd	0.0003	uM
(5Z)-2-(2,6-dichlorophenyl)imino-5-(quinoxalin-6-ylmethylidene)-1,3-thiazolidin-4-one	1947697: Binding affinity to human CLK1 assessed as equilibrium dissociation constant measured upto 240 min by TR-FRET assay	kd	0.0004	uM
(5Z)-5-(1,3-benzothiazol-6-ylmethylidene)-2-[(2R)-1-methoxy-4-methylpentan-2-yl]iminoimidazolidin-4-one	2024541: Binding affinity to human CLK1 assessed as dissociation constant	kd	0.0004	uM
5-(3-chloroanilino)benzo[c][2,6]naphthyridine-8-carboxylic acid	1947697: Binding affinity to human CLK1 assessed as equilibrium dissociation constant measured upto 240 min by TR-FRET assay	kd	0.0005	uM
N-[6-(1-methylpyrazol-4-yl)isoquinolin-3-yl]-1-methylsulfonylpiperidine-4-carboxamide	1947697: Binding affinity to human CLK1 assessed as equilibrium dissociation constant measured upto 240 min by TR-FRET assay	kd	0.0006	uM
4,14,15-trimethoxy-10-azatetracyclo[7.6.1.02,7.012,16]hexadeca-1(15),2(7),3,5,8,13-hexaen-11-one	1947697: Binding affinity to human CLK1 assessed as equilibrium dissociation constant measured upto 240 min by TR-FRET assay	kd	0.0006	uM
4-[2-methyl-1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl]-N-(6-pyridin-4-ylimidazo[1,2-a]pyridin-2-yl)benzamide	1861145: Inhibition of N-terminal FLAG-tagged human Clk1 using myelin basic protein as substrate preincubated for 10 mins followed by ATP addition measured after 45 mins by fluorescence based microplate reader analysis	ic50	0.0007	uM
Abemaciclib	1947697: Binding affinity to human CLK1 assessed as equilibrium dissociation constant measured upto 240 min by TR-FRET assay	kd	0.0009	uM
1-(2-methylpropyl)-N-[6-(1-methylpyrazol-4-yl)isoquinolin-3-yl]piperidine-4-carboxamide	1947697: Binding affinity to human CLK1 assessed as equilibrium dissociation constant measured upto 240 min by TR-FRET assay	kd	0.0010	uM
(5Z)-5-(1,3-benzodioxol-5-ylmethylidene)-2-[(2R)-1-methoxy-4-methylpentan-2-yl]iminoimidazolidin-4-one	2024434: Inhibition of human CLK1 assessed as incorporation of 33Pi using [gamma-33P]-ATP measured after 60 mins by microplate scintillation counting based radiometric analysis	ic50	0.0010	uM
6-(1-hydroxy-2-methylpropan-2-yl)-N-[6-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-2-yl]pyridine-3-carboxamide	1933970: Inhibition of human CLK1	ic50	0.0011	uM
6-tert-butyl-N-(6-pyridin-4-ylimidazo[1,2-a]pyridin-2-yl)pyridine-3-carboxamide	1933970: Inhibition of human CLK1	ic50	0.0011	uM
6-tert-butyl-N-[6-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-2-yl]pyridine-3-carboxamide	1861150: Inhibition of human recombinant GST-tagged Clk1 (129 to 484 residues) expressed in Escherichia coli expression system using GRSRSRSRSRSRSRSR peptide as substrate preincubated for 10 mins followed by ATP addition measured after 30 mins by ADP-Glo assay	ic50	0.0011	uM
4-[3-(4-hydroxyphenyl)-2H-pyrazolo[3,4-b]pyridin-5-yl]benzene-1,2-diol	1947697: Binding affinity to human CLK1 assessed as equilibrium dissociation constant measured upto 240 min by TR-FRET assay	kd	0.0013	uM
(1Z)-1-(3-ethyl-5-hydroxy-1,3-benzothiazol-2-ylidene)propan-2-one	1947697: Binding affinity to human CLK1 assessed as equilibrium dissociation constant measured upto 240 min by TR-FRET assay	kd	0.0013	uM
(2S)-1-[[5-(3-methyl-2H-indazol-5-yl)-3-pyridinyl]oxy]-3-phenylpropan-2-amine	624764: Binding constant for CLK1 kinase domain	kd	0.0014	uM
[4-[[4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl]amino]-3-methoxyphenyl]-(4-morpholin-4-ylpiperidin-1-yl)methanone	1947697: Binding affinity to human CLK1 assessed as equilibrium dissociation constant measured upto 240 min by TR-FRET assay	kd	0.0014	uM
N’-(3,5-difluorophenyl)-5-methoxy-1-benzothiophene-2-carbohydrazide	1994278: Inhibition of human CLK1 using GRSRSRSRSRSRSRS as substrate incubated for 15 mins in presence of ATP by gamma32P-ATP based analysis	ic50	0.0014	uM
5-phenyl-1H-indazole	1947697: Binding affinity to human CLK1 assessed as equilibrium dissociation constant measured upto 240 min by TR-FRET assay	kd	0.0016	uM
N’-(3,5-dichlorophenyl)-5-methoxy-1-benzothiophene-2-carbohydrazide	1994278: Inhibition of human CLK1 using GRSRSRSRSRSRSRS as substrate incubated for 15 mins in presence of ATP by gamma32P-ATP based analysis	ic50	0.0017	uM
(2S)-2-[[6-(6-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)quinazolin-4-yl]amino]-2-phenylethanol	2110575: Inhibition of CLK1 (unknown origin) preincubated with enzyme for 10 mins followed by substrate and ATP addition measured after 60 mins by ADP-Glo reagent based assay	ic50	0.0017	uM
(5Z)-5-(1,3-benzothiazol-6-ylmethylidene)-2-cycloheptyliminoimidazolidin-4-one	1947697: Binding affinity to human CLK1 assessed as equilibrium dissociation constant measured upto 240 min by TR-FRET assay	kd	0.0018	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	1424955: 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	0.0020	uM
5-[1-[(1S)-1-(4-fluorophenyl)ethyl]triazolo[4,5-c]quinolin-8-yl]-1,3-benzoxazole	1446422: Inhibition of recombinant human CLK1 expressed in insect cells using ERMRPRKRQGSVRRRV peptide as substrate after 40 mins in presence of [gamma-33P]-ATP by scintillation counting	ic50	0.0020	uM
4-(1,3-benzodioxol-5-yl)-N-[(3,5-dichlorophenyl)methyl]pyrimidin-2-amine	752772: Inhibition of CLK1 (unknown origin)	ic50	0.0020	uM
5-(2-amino-4-pyridinyl)-N-[(2,6-difluorophenyl)methyl]-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine	1812180: Inhibition of human wild type CLK1 (H129 to S509) expressed in mammalian cells by DiscoveryX Kinomescan binding assay	kd	0.0026	uM
(5Z)-2-(1-adamantylimino)-5-(1,3-benzothiazol-6-ylmethylidene)imidazolidin-4-one	1947697: Binding affinity to human CLK1 assessed as equilibrium dissociation constant measured upto 240 min by TR-FRET assay	kd	0.0026	uM
ethyl 3-[(E)-2-amino-1-cyanoethenyl]-6,7-dichloro-1-methylindole-2-carboxylate	1947697: Binding affinity to human CLK1 assessed as equilibrium dissociation constant measured upto 240 min by TR-FRET assay	kd	0.0028	uM
5-methoxy-N’-(3-methoxyphenyl)-1-benzothiophene-2-carbohydrazide	1994278: Inhibition of human CLK1 using GRSRSRSRSRSRSRS as substrate incubated for 15 mins in presence of ATP by gamma32P-ATP based analysis	ic50	0.0037	uM
(5Z)-5-(1,3-benzothiazol-6-ylmethylidene)-2-[(5-hydroxy-2-adamantyl)imino]imidazolidin-4-one	2010386: Inhibition of N-terminal GST/His6-fused human full length CLK1 (1 to 484 residues) expressed in Sf9 cells assessed as inhibition of autophosphorylation using [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay	ic50	0.0040	uM
N-[(4-methoxyphenyl)methyl]-6-quinolin-6-ylimidazo[1,2-a]pyridine-3-carboxamide	1757108: Inhibition of recombinant human CLK1 (130 to end residues) using ERMRPRKRQGSVR as substrate incubated for 40 mins in presence of [gamma-33ATP] by scintillation counting based radiometry assay	ic50	0.0040	uM
(5Z)-2-(1-adamantylimino)-5-[(2-methylindazol-5-yl)methylidene]imidazolidin-4-one	2010386: Inhibition of N-terminal GST/His6-fused human full length CLK1 (1 to 484 residues) expressed in Sf9 cells assessed as inhibition of autophosphorylation using [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay	ic50	0.0040	uM
N-(4-fluoro-2-methoxybenzoyl)-5-methoxy-1-benzothiophene-2-carboxamide	1861121: Inhibition of human recombinant GST-tagged Clk1 (129 to 484 residues) expressed in Escherichia coli expression system using GRSRSRSRSRSRSRS peptide as substrate incubated for 15 mins in presence of ATP by phosphoimager analysis	ic50	0.0040	uM
2-N-methyl-4-N-(pyrimidin-2-ylmethyl)-5-quinolin-6-yl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine	1851264: Binding affinity to CLK1 (unknown origin) assessed as dissociation constant	kd	0.0048	uM
methyl 2-(2-chloroanilino)-4-hydroxy-5-[(Z)-pyrrolo[2,3-b]pyridin-3-ylidenemethyl]furan-3-carboxylate	1444265: Inhibition of CLK1 (unknown origin) pretreated for 30 mins followed by substrate addition measured after 5 hrs in presence of 1 mM ATP	ic50	0.0050	uM
N’-(4-methoxyphenyl)-6-quinolin-6-ylimidazo[1,2-a]pyridine-3-carbohydrazide	1757108: Inhibition of recombinant human CLK1 (130 to end residues) using ERMRPRKRQGSVR as substrate incubated for 40 mins in presence of [gamma-33ATP] by scintillation counting based radiometry assay	ic50	0.0050	uM
(5Z)-5-(1,3-benzothiazol-6-ylmethylidene)-2-[(1R)-2-methoxy-1-phenylethyl]iminoimidazolidin-4-one	2010386: Inhibition of N-terminal GST/His6-fused human full length CLK1 (1 to 484 residues) expressed in Sf9 cells assessed as inhibition of autophosphorylation using [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay	ic50	0.0050	uM
2-(1-adamantylamino)-5-[(E)-benzimidazol-5-ylidenemethyl]-1H-imidazol-4-ol	2010386: Inhibition of N-terminal GST/His6-fused human full length CLK1 (1 to 484 residues) expressed in Sf9 cells assessed as inhibition of autophosphorylation using [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay	ic50	0.0050	uM
2-(1-adamantylamino)-5-[(E)-indazol-5-ylidenemethyl]-1H-imidazol-4-ol	2010386: Inhibition of N-terminal GST/His6-fused human full length CLK1 (1 to 484 residues) expressed in Sf9 cells assessed as inhibition of autophosphorylation using [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay	ic50	0.0050	uM
N-[3-(5-fluoro-3-pyridinyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-4-(4-methylpiperazin-1-yl)benzamide	2033623: Inhibition of human 130-end recombinant CLK1 assessed as remaining activity using ERMRPRKRQGSVR as substrate by [gamma-32P]ATP binding based scintillation counting based analysis	ic50	0.0050	uM
4-chloro-2-methoxy-N-[3-(5-methoxy-3-pyridinyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]benzamide	2033623: Inhibition of human 130-end recombinant CLK1 assessed as remaining activity using ERMRPRKRQGSVR as substrate by [gamma-32P]ATP binding based scintillation counting based analysis	ic50	0.0050	uM
6,7-dibromo-5-methyl-2-piperazin-1-yl-1,3-diazatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraene	2070979: Inhibition of CLK1 (unknown origin) by ADP-Glo assay	ic50	0.0053	uM
N,N-dimethyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amine	1947697: Binding affinity to human CLK1 assessed as equilibrium dissociation constant measured upto 240 min by TR-FRET assay	kd	0.0054	uM
N’-(3-cyanophenyl)-5-methoxy-1-benzothiophene-2-carbohydrazide	1994278: Inhibition of human CLK1 using GRSRSRSRSRSRSRS as substrate incubated for 15 mins in presence of ATP by gamma32P-ATP based analysis	ic50	0.0054	uM
N-[5-[3-[7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-1H-indazol-5-yl]-3-pyridinyl]-3-methylbutanamide	1947697: Binding affinity to human CLK1 assessed as equilibrium dissociation constant measured upto 240 min by TR-FRET assay	kd	0.0059	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, decreases expression, affects cotreatment, increases abundance, increases expression	7
Air Pollutants	increases expression, affects cotreatment, decreases expression, increases abundance, increases oxidation (+1 more)	3
Cyclosporine	increases expression	3
cobaltous chloride	increases expression	2
Cadmium	increases expression	2
Cisplatin	affects cotreatment, decreases expression, increases expression	2
Ozone	affects cotreatment, decreases expression, increases oxidation, increases abundance, affects expression	2
Tobacco Smoke Pollution	increases expression, affects expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
GSK-J4	increases expression	1
FR900359	decreases phosphorylation	1
dicrotophos	decreases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	decreases expression, increases oxidation, increases abundance, affects cotreatment	1
bisphenol A	increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
2-butenal	increases expression	1
diethyl maleate	increases expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
nickel chloride	increases expression	1
zinc chromate	increases abundance, increases expression	1
potassium nitrate	decreases expression	1
tobacco tar	decreases expression	1
indirubin	decreases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
coumarin	increases phosphorylation	1
cupric oxide	increases expression	1
5-iodotubercidin	decreases activity	1

ChEMBL screening assays

553 unique, capped per target: 547 binding, 4 functional, 2 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4016847	Binding	Inhibition of CLK1/4 in human T24 cells assessed as down regulation of EGFR expression at 10 uM after 3 days by Western blot analysis relative to control	Development of Selective Clk1 and -4 Inhibitors for Cellular Depletion of Cancer-Relevant Proteins. — J Med Chem
CHEMBL4263635	ADMET	Inhibition of recombinant human Clk1 expressed in Escherichia coli at 2 uM by Z’-LYTE assay	Development of novel 2,4-bispyridyl thiophene-based compounds as highly potent and selective Dyrk1A inhibitors. Part I: Benzamide and benzylamide derivatives. — Eur J Med Chem
CHEMBL5209986	Functional	Affinity Phenotypic Cellular interaction (Changed alternative splicing pattern determined by mRNAseq) EUB0000321b CLK1	Affinity Phenotypic Cellular Literature for EUbOPEN Chemogenomics Library wave 3

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1NH	Abcam HeLa CLK1 KO	Cancer cell line	Female
CVCL_D9C3	Ubigene HEK293 CLK1 KO	Transformed cell line	Female
CVCL_SJ18	HAP1 CLK1 (-) 1	Cancer cell line	Male
CVCL_SJ19	HAP1 CLK1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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