HIPK4

Summary

HIPK4 (homeodomain interacting protein kinase 4, HGNC:19007) is a protein-coding gene on chromosome 19q13.2, encoding Homeodomain-interacting protein kinase 4 (Q8NE63). Protein kinase that phosphorylates human TP53 at Ser-9, and thus induces TP53 repression of BIRC5 promoter.

This gene encodes a member of the homeodomain interacting protein kinase (HIPK) family of proteins. While other members of this family are found throughout vertebrates, this member is present only in mammals. Compared to other members of this family, the encoded protein lacks a nuclear localization signal and a C-terminal autoinhibitory domain. The encoded protein exhibits kinase activity and may phosphorylate the tumor suppressor protein p53.

Source: NCBI Gene 147746 — RefSeq curated summary.

At a glance

• Gene–disease (curated): male infertility with azoospermia or oligozoospermia due to single gene mutation (Moderate, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 111 total — 1 likely-pathogenic
• Druggable target: yes — 37 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_144685

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19007
Approved symbol	HIPK4
Name	homeodomain interacting protein kinase 4
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ32818
Ensembl gene	ENSG00000160396
Ensembl biotype	protein_coding
OMIM	611712
Entrez	147746

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000291823

RefSeq mRNA: 1 — MANE Select: NM_144685 NM_144685

CCDS: CCDS12555

Canonical transcript exons

ENST00000291823 — 4 exons

Exon	Start	End
ENSE00001114462	40383783	40384139
ENSE00001227861	40380323	40381168
ENSE00001227881	40379271	40379769
ENSE00001227890	40389438	40390181

Expression profiles

Bgee: expression breadth ubiquitous, 117 present calls, max score 90.97.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0360 / max 36.5379, expressed in 3 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
180983	0.0213	3
180984	0.0146	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.97	gold quality
left testis	UBERON:0004533	80.41	gold quality
right testis	UBERON:0004534	79.55	gold quality
nucleus accumbens	UBERON:0001882	78.63	gold quality
testis	UBERON:0000473	78.41	gold quality
putamen	UBERON:0001874	77.73	gold quality
caudate nucleus	UBERON:0001873	77.09	gold quality
right frontal lobe	UBERON:0002810	76.61	gold quality
prefrontal cortex	UBERON:0000451	75.83	gold quality
oocyte	CL:0000023	75.23	gold quality
Brodmann (1909) area 9	UBERON:0013540	74.50	gold quality
tendon of biceps brachii	UBERON:0008188	72.63	silver quality
frontal cortex	UBERON:0001870	72.49	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	72.08	gold quality
anterior cingulate cortex	UBERON:0009835	71.96	gold quality
neocortex	UBERON:0001950	71.08	gold quality
sperm	CL:0000019	70.05	gold quality
amygdala	UBERON:0001876	69.60	gold quality
cerebral cortex	UBERON:0000956	69.38	gold quality
secondary oocyte	CL:0000655	68.56	gold quality
right hemisphere of cerebellum	UBERON:0014890	67.46	gold quality
cerebellar cortex	UBERON:0002129	66.95	gold quality
cerebellar hemisphere	UBERON:0002245	66.93	gold quality
Ammon’s horn	UBERON:0001954	66.90	gold quality
forebrain	UBERON:0001890	66.53	gold quality
cerebellum	UBERON:0002037	66.41	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	65.97	gold quality
primary visual cortex	UBERON:0002436	65.52	gold quality
brain	UBERON:0000955	65.22	gold quality
upper leg skin	UBERON:0004262	64.95	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.41

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP53

miRNA regulators (miRDB)

29 targeting HIPK4, 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-6759-5P	99.99	66.54	785
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-6507-5P	99.36	70.46	2524
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-3190-5P	98.87	64.89	1345
HSA-MIR-760	98.81	66.65	1392
HSA-MIR-4782-5P	98.35	69.33	1474
HSA-MIR-5706	98.35	69.33	1463
HSA-MIR-4277	98.34	67.17	1323
HSA-MIR-92A-1-5P	98.28	64.51	631
HSA-MIR-6779-3P	97.51	65.82	789
HSA-MIR-4640-5P	97.42	66.33	1543
HSA-MIR-3173-5P	97.35	65.82	1282
HSA-MIR-6799-3P	97.35	65.60	1302
HSA-MIR-4726-5P	97.24	65.67	1299
HSA-MIR-6822-3P	96.60	66.06	680
HSA-MIR-3918	96.13	64.65	1300
HSA-MIR-6888-5P	95.89	63.78	831
HSA-MIR-3943	95.87	64.57	523

Literature-anchored findings (GeneRIF, showing 4)

• homeodomain interacting protein kinase 4 could phosphorylate human p53 protein at serine 9, both in vitro and in vivo (PMID:18022393)
• Analysis of these mutants revealed that HIPK1, HIPK2 and HIPK3 but not HIPK4 are capable of autophosphorylating on other tyrosines (PMID:25630557)
• loss of HIPK4 expression improves early skin epithelial differentiation accompanied by an increase in K8 and K18 expression, and improves late keratinocyte differentiation with an increase of epidermal identity (PMID:28966120)
• Homeodomain-interacting protein kinase HIPK4 regulates phosphorylation of manchette protein RIMBP3 during spermiogenesis. (PMID:35931115)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hipk4	ENSMUSG00000040424
rattus_norvegicus	Hipk4	ENSRNOG00000020835
drosophila_melanogaster	Dyrk3	FBGN0027101
drosophila_melanogaster	mnb	FBGN0259168
caenorhabditis_elegans		WBGENE00003149
caenorhabditis_elegans		WBGENE00003150
caenorhabditis_elegans		WBGENE00013727
caenorhabditis_elegans		WBGENE00185089

Paralogs (12): DYRK4 (ENSG00000010219), CLK1 (ENSG00000013441), HIPK2 (ENSG00000064393), DYRK1B (ENSG00000105204), HIPK3 (ENSG00000110422), CLK4 (ENSG00000113240), DYRK2 (ENSG00000127334), DYRK3 (ENSG00000143479), DYRK1A (ENSG00000157540), HIPK1 (ENSG00000163349), CLK2 (ENSG00000176444), CLK3 (ENSG00000179335)

Protein

Protein identifiers

Homeodomain-interacting protein kinase 4 — Q8NE63 (reviewed: Q8NE63)

All UniProt accessions (2): Q8NE63, A0A140VJL1

UniProt curated annotations — full annotation on UniProt →

Function. Protein kinase that phosphorylates human TP53 at Ser-9, and thus induces TP53 repression of BIRC5 promoter. May act as a corepressor of transcription factors (Potential).

Subcellular location. Cytoplasm.

Post-translational modifications. Autophosphorylated.

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

RefSeq proteins (1): NP_653286* (*=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
IPR050494	Ser_Thr_dual-spec_kinase	Family

Pfam: PF00069

Catalyzed reactions (Rhea), 2 shown:

• 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 (19 total): sequence variant 8, sequence conflict 3, binding site 2, chain 1, domain 1, region of interest 1, compositionally biased region 1, active site 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NE63-F1	70.45	0.52

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): 136 (proton acceptor)

Ligand- & substrate-binding residues (2): 17–25; 40

Post-translational modifications (1): 511

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 32 (showing top): GOBP_SIGNAL_TRANSDUCTION_BY_P53_CLASS_MEDIATOR, GOBP_REGULATION_OF_SIGNAL_TRANSDUCTION_BY_P53_CLASS_MEDIATOR, GOBP_CHROMATIN_REMODELING, GOMF_PROTEIN_KINASE_ACTIVITY, GOMF_KINASE_ACTIVITY, GOMF_PROTEIN_SERINE_THREONINE_KINASE_ACTIVITY, GOMF_ADENYL_NUCLEOTIDE_BINDING, GOMF_HISTONE_KINASE_ACTIVITY, GOMF_TRANSFERASE_ACTIVITY_TRANSFERRING_PHOSPHORUS_CONTAINING_GROUPS, MIKKELSEN_IPS_LCP_WITH_H3K4ME3, GLI4_TARGET_GENES, ZNF16_TARGET_GENES, ZNF92_TARGET_GENES, MIR6507_5P, MIR3686

GO Biological Process (3): regulation of signal transduction by p53 class mediator (GO:1901796), chromatin remodeling (GO:0006338), protein phosphorylation (GO:0006468)

GO Molecular Function (11): protein serine/threonine kinase activity (GO:0004674), protein tyrosine kinase activity (GO:0004713), ATP binding (GO:0005524), histone kinase activity (GO:0035173), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), DNA binding (GO:0003677), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein kinase activity	4
signal transduction by p53 class mediator	1
regulation of intracellular signal transduction	1
chromatin organization	1
phosphorylation	1
protein modification process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
histone modifying activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
nucleic acid 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
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1110 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HIPK4	DPY19L2	Q6NUT2	506
HIPK4	MBP	P02686	485
HIPK4	RITA1	Q96K30	469
HIPK4	ACTR6	Q9GZN1	455
HIPK4	SPACA1	Q9HBV2	435
HIPK4	TTC9B	Q8N6N2	428
HIPK4	BIRC5	O15392	424
HIPK4	MEF2C	Q06413	424
HIPK4	ZPBP	Q9BS86	415
HIPK4	PLD3	Q8IV08	410
HIPK4	BNIP5	P0C671	409
HIPK4	TP63	Q9H3D4	405
HIPK4	CDKN2B	P42772	405
HIPK4	NFYB	P25208	399
HIPK4	IRGQ	Q8WZA9	395

IntAct

10 interactions, top by confidence:

A	B	Type	Score
HIPK4	APPBP2	psi-mi:“MI:0915”(physical association)	0.560
APPBP2	HIPK4	psi-mi:“MI:0915”(physical association)	0.560
HSP90AB1	HIPK4	psi-mi:“MI:0915”(physical association)	0.560
HIPK4	YWHAE	psi-mi:“MI:0915”(physical association)	0.400
SFN	HIPK4	psi-mi:“MI:0915”(physical association)	0.400
HIPK4	HSP90AA1	psi-mi:“MI:0914”(association)	0.350
HIPK4	CDIPT	psi-mi:“MI:0914”(association)	0.350

BioGRID (38): HIPK4 (Two-hybrid), HIPK4 (Two-hybrid), HSP90AA1 (Affinity Capture-MS), HSP90AB1 (Affinity Capture-MS), BAG6 (Affinity Capture-MS), CCT3 (Affinity Capture-MS), FKBP5 (Affinity Capture-MS), CDC37 (Affinity Capture-MS), CCT7 (Affinity Capture-MS), SLC25A10 (Affinity Capture-MS), HIPK4 (Affinity Capture-Luminescence), AKAP8 (Affinity Capture-MS), EEF2 (Affinity Capture-MS), TECR (Affinity Capture-MS), SFXN2 (Affinity Capture-MS)

ESM2 similar proteins: A0AUV4, A0JM98, A1A5Q6, A2KF29, B1WAS2, C0HKC8, C0HKC9, O60285, O70551, O88866, P51957, P57058, P57059, Q2T9U5, Q4R9F7, Q5R7G9, Q5RD27, Q5REX1, Q5XHI9, Q60670, Q641K5, Q66HE5, Q68UT7, Q6IFT4, Q6P3R8, Q6REY9, Q6VZ17, Q80VH0, Q8BI55, Q8BLD6, Q8BZN4, Q8C0N0, Q8C0V7, Q8C0X8, Q8CFH6, Q8NE63, Q8TF76, Q96SB4, Q9H093, Q9H0K1

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

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	95
Likely benign	8
Benign	4

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
4813336	NM_144685.5(HIPK4):c.1A>G (p.Met1Val)	Likely pathogenic

SpliceAI

326 predictions. Top by Δscore:

Variant	Effect	Δscore
19:40379768:CT:C	acceptor_gain	1.0000
19:40380318:CTCA:C	donor_loss	1.0000
19:40380320:CACCT:C	donor_loss	1.0000
19:40381164:CGCAC:C	acceptor_gain	1.0000
19:40381166:CAC:C	acceptor_gain	1.0000
19:40381167:AC:A	acceptor_gain	1.0000
19:40381168:CC:C	acceptor_gain	1.0000
19:40381168:CCT:C	acceptor_loss	1.0000
19:40381178:CA:C	acceptor_gain	1.0000
19:40381179:A:AC	acceptor_gain	1.0000
19:40381179:A:C	acceptor_gain	1.0000
19:40383777:CCTTA:C	donor_loss	1.0000
19:40383779:TTA:T	donor_loss	1.0000
19:40383780:TA:T	donor_loss	1.0000
19:40383781:A:AC	donor_gain	1.0000
19:40383781:AC:A	donor_gain	1.0000
19:40383781:ACCTT:A	donor_gain	1.0000
19:40383782:C:CG	donor_gain	1.0000
19:40383782:CC:C	donor_gain	1.0000
19:40383782:CCT:C	donor_gain	1.0000
19:40383782:CCTT:C	donor_gain	1.0000
19:40383782:CCTTC:C	donor_gain	1.0000
19:40384144:C:CT	acceptor_gain	1.0000
19:40389434:TCAC:T	donor_loss	1.0000
19:40389436:A:AC	donor_gain	1.0000
19:40389436:ACC:A	donor_loss	1.0000
19:40389437:C:CC	donor_gain	1.0000
19:40379766:GCCT:G	acceptor_gain	0.9900
19:40379767:CCTC:C	acceptor_gain	0.9900
19:40379768:CTCTG:C	acceptor_loss	0.9900

AlphaMissense

4060 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:40384000:C:T	G202D	1.000
19:40384001:C:G	G202R	1.000
19:40384010:A:G	W199R	1.000
19:40384010:A:T	W199R	1.000
19:40384131:G:C	D158E	1.000
19:40384131:G:T	D158E	1.000
19:40384132:T:A	D158V	1.000
19:40384132:T:G	D158A	1.000
19:40384133:C:G	D158H	1.000
19:40389480:G:C	N141K	1.000
19:40389480:G:T	N141K	1.000
19:40389481:T:A	N141I	1.000
19:40389481:T:C	N141S	1.000
19:40389481:T:G	N141T	1.000
19:40389482:T:A	N141Y	1.000
19:40389482:T:C	N141D	1.000
19:40389482:T:G	N141H	1.000
19:40389489:C:A	K138N	1.000
19:40389489:C:G	K138N	1.000
19:40389491:T:C	K138E	1.000
19:40389493:A:T	L137H	1.000
19:40389496:T:A	D136V	1.000
19:40389496:T:G	D136A	1.000
19:40389783:C:A	K40N	1.000
19:40389783:C:G	K40N	1.000
19:40389785:T:C	K40E	1.000
19:40389837:G:C	F22L	1.000
19:40389837:G:T	F22L	1.000
19:40389839:A:G	F22L	1.000
19:40380988:G:T	R335S	0.999

dbSNP variants (sampled 300 via entrez): RS1000055875 (19:40384458 C>T), RS1000109127 (19:40380895 G>A), RS1000172461 (19:40387591 G>A), RS1000386301 (19:40390086 G>A), RS1000545369 (19:40379936 G>A), RS1000681211 (19:40392014 C>T), RS1000760617 (19:40391737 G>C), RS1000948508 (19:40385710 G>C,T), RS1001172045 (19:40389151 G>A), RS1001204776 (19:40388879 T>C), RS1001333963 (19:40378914 C>G,T), RS1001674382 (19:40390780 G>A,C), RS1002203998 (19:40379993 G>A), RS1002300075 (19:40386600 C>T), RS1002591936 (19:40386359 T>C)

Disease associations

OMIM: gene MIM:611712 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
male infertility with azoospermia or oligozoospermia due to single gene mutation	Moderate	Autosomal recessive

Mondo (3): prostate cancer (MONDO:0008315), male infertility (MONDO:0005372), (MONDO:0018393)

Orphanet (1): Familial prostate cancer (Orphanet:1331)

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST003827_4	Otitis media	2.000000e-07
GCST003828_1	Otitis media (chronic)	3.000000e-08
GCST003829_4	Otitis media (recurrent)	1.000000e-07

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D007248	Infertility, Male	C12.100.500.430; C12.100.750.700; C12.200.294.430
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1075167 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

37 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 624,091 (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
CHEMBL1173655	AFATINIB	4	15,144
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL180022	NERATINIB	4	9,404
CHEMBL2105712	AFATINIB DIMALEATE	4	3,215
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL553	ERLOTINIB	4	108,300
CHEMBL576982	QUIZARTINIB	4	4,432
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL939	GEFITINIB	4	117,814
CHEMBL941	IMATINIB	4	111,611
CHEMBL223360	LINIFANIB	3	3,925
CHEMBL300138	ENZASTAURIN	3	3,209
CHEMBL31965	CANERTINIB	3	8,083
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL603469	LESTAURTINIB	3
CHEMBL91829	RUBOXISTAURIN	3	77
CHEMBL1230609	FORETINIB	2
CHEMBL124660	TANDUTINIB	2
CHEMBL1721885	SU-014813	2
CHEMBL1738757	REBASTINIB	2
CHEMBL1967878	CENISERTIB	2
CHEMBL1980297	ILORASERTIB	2
CHEMBL215152	DEFOSBARASERTIB	2
CHEMBL475251	R-406	2
CHEMBL513909	BI-2536	2
CHEMBL521851	PICTILISIB	2

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — HIPK subfamily

ChEMBL bioactivities

365 potent at pChembl≥5 of 366 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.29	Kd	0.51	nM	FORETINIB
8.57	Kd	2.7	nM	SORAFENIB
8.55	IC50	2.8	nM	CHEMBL4855209
8.52	IC50	3	nM	SORAFENIB
8.48	IC50	3.3	nM	CHEMBL4859179
8.48	Kd	3.3	nM	SORAFENIB
8.41	Kd	3.9	nM	AST-487
8.40	Ki	3.981	nM	CHEMBL2004716
8.40	Ki	3.981	nM	CHEMBL2000335
8.30	Ki	5.012	nM	CHEMBL411903
8.29	IC50	5.1	nM	CHEMBL4850066
8.28	IC50	5.2	nM	CHEMBL4855979
8.20	Ki	6.31	nM	SNS-314
8.10	Ki	7.943	nM	CHEMBL1983932
8.02	IC50	9.6	nM	CHEMBL4870763
8.00	Ki	10	nM	CHEMBL1992306
8.00	Ki	10	nM	CHEMBL1988387
8.00	Ki	10	nM	SORAFENIB
8.00	Ki	10	nM	CHEMBL1984162
8.00	Ki	10	nM	CHEMBL371206
8.00	Ki	10	nM	CHEMBL1982466
7.96	Kd	11	nM	CHEMBL4571241
7.90	Ki	12.59	nM	CHEMBL213505
7.90	Ki	12.59	nM	CHEMBL1998585
7.90	Ki	12.59	nM	CHEMBL1967116
7.90	Ki	12.59	nM	CHEMBL1988717
7.90	Ki	12.59	nM	CHEMBL497151
7.90	Ki	12.59	nM	CHEMBL272453
7.90	Ki	12.59	nM	CHEMBL1979577
7.90	Ki	12.59	nM	CHEMBL2005631
7.80	Ki	15.85	nM	CHEMBL1970074
7.80	Ki	15.85	nM	CHEMBL1965988
7.80	Ki	15.85	nM	CHEMBL271381
7.72	IC50	19	nM	CHEMBL4874174
7.70	Ki	19.95	nM	CHEMBL1973211
7.70	Ki	19.95	nM	CHEMBL1979883
7.70	Ki	19.95	nM	CHEMBL396523
7.70	Ki	19.95	nM	ILORASERTIB
7.64	IC50	23	nM	CHEMBL4847460
7.60	Ki	25.12	nM	CHEMBL1970142
7.60	Ki	25.12	nM	CHEMBL1998159
7.60	Ki	25.12	nM	CHEMBL1989708
7.60	Ki	25.12	nM	CHEMBL1981725
7.50	IC50	32	nM	CHEMBL4875968
7.50	Ki	31.62	nM	CHEMBL1994321
7.50	Ki	31.62	nM	CHEMBL1966816
7.50	Ki	31.62	nM	CHEMBL1973937
7.40	IC50	40	nM	CHEMBL3103192
7.40	Ki	39.81	nM	LINIFANIB
7.40	Ki	39.81	nM	CHEMBL1968406

PubChem BioAssay actives

65 with measured affinity, of 273 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
1-N’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	624720: Binding constant for HIPK4 kinase domain	kd	0.0005	uM
Sorafenib	507972: Binding affinity to HIPK4	kd	0.0027	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	624720: Binding constant for HIPK4 kinase domain	kd	0.0039	uM
N-[4-(6,7-dimethoxyquinazolin-4-yl)oxy-3-fluorophenyl]-6-ethyl-1,2-dimethyl-4-oxoquinoline-3-carboxamide	1626963: Binding affinity to human HIPk4	kd	0.0110	uM
N-[2-[2-aminoethyl(methyl)amino]-5-[[3-cyano-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-yl]amino]phenyl]acetamide	1301615: Inhibition of Hipk4 (unknown origin) by quantitative PCR	ic50	0.0400	uM
1-[4-(3-amino-1H-indazol-4-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea	624720: Binding constant for HIPK4 kinase domain	kd	0.0460	uM
2-[3-[[7-[3-[ethyl(2-hydroxyethyl)amino]propoxy]quinazolin-4-yl]amino]-1H-pyrazol-5-yl]-N-(3-fluorophenyl)acetamide	624720: Binding constant for HIPK4 kinase domain	kd	0.0970	uM
(3Z)-5-[(2,6-dichlorophenyl)methylsulfonyl]-3-[[3,5-dimethyl-4-[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carbonyl]-1H-pyrrol-2-yl]methylidene]-1H-indol-2-one	1733114: Inhibition of HIPK4 (unknown origin)	ic50	0.1000	uM
(18S)-18-[(dimethylamino)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.17,14.02,6.08,13.022,27]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione	1733114: Inhibition of HIPK4 (unknown origin)	ic50	0.1000	uM
1-(5-tert-butyl-1,2-oxazol-3-yl)-3-[4-(6,7,8,9-tetrahydropyrimido[5,4-b][1,4]oxazepin-4-ylamino)phenyl]urea	1735630: Inhibition of human HIPK4 using RRRFRPASPLRGPPK as substrate after 40 mins by [gamma-33ATP] radiometric assay	ic50	0.1270	uM
Bosutinib	624720: Binding constant for HIPK4 kinase domain	kd	0.1300	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	1715321: Inhibition of human HIPK4 using MBP as substrate by [gamma-33P]-ATP assay	ic50	0.1380	uM
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	507972: Binding affinity to HIPK4	kd	0.1500	uM
Sunitinib	507972: Binding affinity to HIPK4	kd	0.1600	uM
6-(5-methyl-1H-pyrazol-4-yl)-2-[(2S)-piperidin-2-yl]-3H-thieno[3,2-d]pyrimidin-4-one;dihydrochloride	1528740: Inhibition of recombinant full-length human N-terminal GST-tagged HIPK4 expressed in baculovirus expression system by Z’-LYTE assay	ic50	0.1760	uM
Fedratinib	624720: Binding constant for HIPK4 kinase domain	kd	0.2200	uM
2-[6-(1-benzothiophen-2-yl)thieno[2,3-d]pyrimidin-4-yl]sulfanylacetic acid	1718378: Binding affinity to human HIPK4 by KINOMEscan scanMAX assay	kd	0.2900	uM
Gefitinib	624720: Binding constant for HIPK4 kinase domain	kd	0.3100	uM
Quizartinib	507972: Binding affinity to HIPK4	kd	0.3200	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	624720: Binding constant for HIPK4 kinase domain	kd	0.3500	uM
Afatinib	624720: Binding constant for HIPK4 kinase domain	kd	0.3600	uM
4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinazolin-4-yl]-N-(4-propan-2-yloxyphenyl)piperazine-1-carboxamide	507972: Binding affinity to HIPK4	kd	0.4000	uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526225: Binding affinity to recombinant full-length N-terminal His-FLAG-tagged HIPK4 (unknown origin) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.4240	uM
4-[4-[(3-tert-butyl-1-quinolin-6-ylpyrazol-5-yl)carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide	2168242: Inhibition of human wild type HIPK4 using RBER-IRStide as substrate preincubated for 2 hrs followed by ATP addition and measured every 2 mins for 2.5 hrs by spectrophotometric analysis	ic50	0.4500	uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]-methylamino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526225: Binding affinity to recombinant full-length N-terminal His-FLAG-tagged HIPK4 (unknown origin) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.4720	uM
1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine	624720: Binding constant for HIPK4 kinase domain	kd	0.5600	uM
(5Z)-5-(1,3-benzothiazol-6-ylmethylidene)-2-[(2R)-1-methoxy-4-methylpentan-2-yl]iminoimidazolidin-4-one	2024509: Inhibition of human HIPK4 assessed as remaining activity by eurofins-cerep kinase profiler analysis	ic50	0.6200	uM
methyl N-[4-[5-[(2S)-2-amino-2,4-dimethylpentoxy]-6-(difluoromethyl)-2-pyridinyl]-2-pyridinyl]carbamate	1904673: Inhibition of HIPK4 (unknown origin)	ic50	0.6500	uM
(2S)-1-[[5-(3-methyl-2H-indazol-5-yl)-3-pyridinyl]oxy]-3-phenylpropan-2-amine	624720: Binding constant for HIPK4 kinase domain	kd	0.7600	uM
Midostaurin	507972: Binding affinity to HIPK4	kd	0.9500	uM
Erlotinib	624720: Binding constant for HIPK4 kinase domain	kd	0.9600	uM
Imatinib	624720: Binding constant for HIPK4 kinase domain	kd	0.9600	uM
5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	624720: Binding constant for HIPK4 kinase domain	kd	0.9700	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	624720: Binding constant for HIPK4 kinase domain	kd	1.0000	uM
Momelotinib	2183897: Inhibition of HIPK4 (unknown origin)	ic50	1.0000	uM
methyl N-[4-[5-[(2S)-2-amino-2,4-dimethylpentoxy]-6-chloro-2-pyridinyl]-2-pyridinyl]carbamate	1904673: Inhibition of HIPK4 (unknown origin)	ic50	1.1000	uM
N-[4-(3-chloro-4-fluoroanilino)-7-(3-morpholin-4-ylpropoxy)quinazolin-6-yl]prop-2-enamide	624720: Binding constant for HIPK4 kinase domain	kd	1.1000	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	624720: Binding constant for HIPK4 kinase domain	kd	1.2000	uM
3-(1-methylindol-3-yl)-4-[1-[1-(pyridin-2-ylmethyl)piperidin-4-yl]indol-3-yl]pyrrole-2,5-dione	624720: Binding constant for HIPK4 kinase domain	kd	1.2000	uM
2-[[2-[[1-[2-(dimethylamino)acetyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide	624720: Binding constant for HIPK4 kinase domain	kd	1.2000	uM
methyl N-[4-[6-[(2S)-2-amino-2,4-dimethylpentoxy]-5-chloro-3-pyridinyl]-2-pyridinyl]carbamate	1904673: Inhibition of HIPK4 (unknown origin)	ic50	1.3000	uM
Neratinib	624720: Binding constant for HIPK4 kinase domain	kd	1.5000	uM
methyl N-[4-[6-[(2S)-2-amino-2,4-dimethylpentoxy]-5-methyl-3-pyridinyl]-2-pyridinyl]carbamate	1904673: Inhibition of HIPK4 (unknown origin)	ic50	1.8000	uM
4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide	624720: Binding constant for HIPK4 kinase domain	kd	2.0000	uM
2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]chromen-4-one	624720: Binding constant for HIPK4 kinase domain	kd	2.0000	uM
2-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol	624720: Binding constant for HIPK4 kinase domain	kd	2.2000	uM
(2R)-2-amino-4,4-dimethyl-N-[3-methyl-4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl]pentanamide	2100160: Inhibition of human full length recombinant HIPK4 using RRRFRPASPLRGP as substrate incubated for 120 mins by [33P]-gammaATP based Radiometric scintillation counting analysis	ic50	2.2750	uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	624720: Binding constant for HIPK4 kinase domain	kd	2.8000	uM
Crizotinib	624720: Binding constant for HIPK4 kinase domain	kd	3.6000	uM
4-[2-(1H-indazol-4-yl)-6-[(4-methylsulfonylpiperazin-1-yl)methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine	624720: Binding constant for HIPK4 kinase domain	kd	5.0000	uM

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
daidzein	affects cotreatment, decreases expression	1
daidzin	affects cotreatment, decreases expression	1
butyraldehyde	decreases expression	1
genistin	affects cotreatment, decreases expression	1
glycitein	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
glycitin	affects cotreatment, decreases expression	1
abrine	decreases expression	1
licochalcone B	increases expression	1
Arsenic	affects methylation	1
Cadmium	decreases expression, increases abundance	1
Silicon Dioxide	increases expression	1
Triclosan	decreases expression	1
Valproic Acid	increases methylation	1
Cadmium Chloride	decreases expression, increases abundance	1
Genistein	decreases expression, affects cotreatment	1

ChEMBL screening assays

211 unique, capped per target: 210 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1100492	Binding	Inhibition of HIPK4 at 10 uM	Discovery of N-substituted pyridinones as potent and selective inhibitors of p38 kinase. — Bioorg Med Chem Lett
CHEMBL1963818	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: HIPK4	PubChem BioAssay data set

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer