HIPK2

Summary

HIPK2 (homeodomain interacting protein kinase 2, HGNC:14402) is a protein-coding gene on chromosome 7q34, encoding Homeodomain-interacting protein kinase 2 (Q9H2X6). Serine/threonine-protein kinase involved in transcription regulation, p53/TP53-mediated cellular apoptosis and regulation of the cell cycle.

This gene encodes a conserved serine/threonine kinase that is a member of the homeodomain-interacting protein kinase family. The encoded protein interacts with homeodomain transcription factors and many other transcription factors such as p53, and can function as both a corepressor and a coactivator depending on the transcription factor and its subcellular localization. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 28996 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 67 total
• Druggable target: yes — 30 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_022740

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14402
Approved symbol	HIPK2
Name	homeodomain interacting protein kinase 2
Location	7q34
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000064393
Ensembl biotype	protein_coding
OMIM	606868
Entrez	28996

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000342645, ENST00000406875, ENST00000428878, ENST00000907407

RefSeq mRNA: 2 — MANE Select: NM_022740 NM_001113239, NM_022740

CCDS: CCDS75666, CCDS75667

Canonical transcript exons

ENST00000406875 — 15 exons

Exon	Start	End
ENSE00000833475	139631165	139631284
ENSE00000833477	139628953	139629039
ENSE00000833479	139626601	139626785
ENSE00000833481	139620401	139620563
ENSE00000833482	139614286	139614493
ENSE00000833485	139613202	139613323
ENSE00000833487	139604081	139604223
ENSE00000833488	139600417	139600596
ENSE00000833490	139596717	139596998
ENSE00000833492	139575128	139575288
ENSE00001378521	139583817	139584064
ENSE00001624166	139631602	139631725
ENSE00001763607	139715932	139717015
ENSE00001875629	139777605	139777998
ENSE00001884346	139561570	139573397

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 99.70.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 40.6477 / max 1628.2246, expressed in 1800 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
86522	29.8583	1789
86521	5.9026	1482
86506	0.9411	331
86507	0.7280	251
86497	0.6394	244
86520	0.6143	341
86514	0.5750	250
86499	0.4886	166
86515	0.3974	185
86519	0.2751	130

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
medial globus pallidus	UBERON:0002477	99.70	gold quality
globus pallidus	UBERON:0001875	99.68	gold quality
inferior vagus X ganglion	UBERON:0005363	99.64	gold quality
ventral tegmental area	UBERON:0002691	99.57	gold quality
subthalamic nucleus	UBERON:0001906	99.56	gold quality
lateral globus pallidus	UBERON:0002476	99.53	gold quality
superior vestibular nucleus	UBERON:0007227	99.53	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.34	gold quality
renal medulla	UBERON:0000362	99.19	gold quality
substantia nigra pars compacta	UBERON:0001965	99.13	gold quality
medulla oblongata	UBERON:0001896	99.05	gold quality
pons	UBERON:0000988	98.80	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.32	gold quality
parietal lobe	UBERON:0001872	98.27	gold quality
postcentral gyrus	UBERON:0002581	98.11	gold quality
esophagus squamous epithelium	UBERON:0006920	97.94	gold quality
pylorus	UBERON:0001166	97.61	gold quality
entorhinal cortex	UBERON:0002728	97.58	gold quality
dorsal plus ventral thalamus	UBERON:0001897	97.56	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.56	gold quality
adult organism	UBERON:0007023	97.49	gold quality
tibia	UBERON:0000979	97.47	gold quality
caput epididymis	UBERON:0004358	97.26	gold quality
jejunal mucosa	UBERON:0000399	97.21	gold quality
Ammon’s horn	UBERON:0001954	97.21	gold quality
pigmented layer of retina	UBERON:0001782	97.13	gold quality
heart right ventricle	UBERON:0002080	97.13	gold quality
amygdala	UBERON:0001876	97.07	gold quality
temporal lobe	UBERON:0001871	97.02	gold quality
corpus callosum	UBERON:0002336	96.97	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	40.99
E-HCAD-10	yes	34.71
E-CURD-119	yes	11.71
E-CURD-114	yes	8.77
E-GEOD-135922	yes	8.18
E-GEOD-93593	yes	4.55
E-MTAB-7249	no	4993.20
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

9 targets.

Target	Regulation
ABCB1	Unknown
CDKN1A	Activation
CTBP2	Unknown
HIF1A	Repression
MEF2C	Repression
NOX1	Repression
TP53	Unknown
VEGFA	Repression
VIM	Repression

Upstream regulators (CollecTRI, top): CEBPB, GATA1, HIF1A, PAX6, PDX1, PML, POU4F1, TP53

miRNA regulators (miRDB)

347 targeting HIPK2, 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-3646	100.00	73.56	5283
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-12136	99.98	72.81	5713

Literature-anchored findings (GeneRIF, showing 40)

• selectively phosphorylates p53 at Ser 46, thus facilitating the CBP-mediated acetylation of p53 at Lys 382, and promoting p53-dependent gene expression (PMID:11740489)
• Identification and characterization; modulates functions of the p53 family in vivo. (PMID:11925430)
• overexpressed wildtype HIPK2 and a kinase defective mutant of HIPK2 directly interact with RanBPM in the nucleus of mammalian cells. (PMID:12220523)
• TP53INP1s and HIPK2 could be partners in regulating p53 activity. (PMID:12851404)
• HIPK2, together with c-Ski, plays an important role in the negative regulation of BMP-induced transcriptional activation (PMID:12874272)
• HIPK2-mediated enhancement of p53-dependent transcription, p53 serine 46 phosphorylation and the antiproliferative function of HIPK2 strictly rely on the presence of PML. (PMID:12907596)
• a novel function for Sp100 as a coactivator for HIPK2-mediated p53 activation. (PMID:14647468)
• HIPK2 participates in the TGF-beta signaling pathway leading to JNK activation and apoptosis in hepatoma cells. (PMID:14678985)
• US11 of herpes simplex virus interacts with HIPK2 through the PEST domain of HIPK2 and this interaction modifies the subcellular distribution of HIPK2 and protects the cell against the HIPK2-induced cell growth arrest (PMID:14990717)
• HIPK2 neutralizes MDM2 inhibition rescuing p53 transcriptional activity and apoptotic function. (PMID:15122315)
• the mechanisms by which the HIPK2/p53 pathway promotes apoptosis and suppression of tumorigenesis. (PMID:15122315)
• Homeodomain-interacting protein kinase-2 (HIPK2) mediates CtBP phosphorylation and degradation in UV-triggered apoptosis. (PMID:15708980)
• a non-sumoylatable HIPK2 mutant displays a strongly increased protein stability (PMID:15766567)
• phosphorylation-dependent sumoylation enables HIPK2 to drive different target gene transcription by means of differential interactions with its binding partners (PMID:15896780)
• HIPK2 effector function on JNK is modulated through dynamic SUMO-1 modification (PMID:15958389)
• HIPK2 contributes to drug-induced modulation of MDM2 activity at transcriptional (through p53Ser46 phosphorylation) and posttranscriptional (through p53-independent subcellular re-localization and proteasomal degradation) levels. (PMID:16212962)
• HIPK2 is a target for SENP1 desumoylation regulated by the cytoplasmic-nuclear shuttling of SENP1. (PMID:16253240)
• Overall, our findings indicate that FHL2 can also regulate p53 via a direct association with HIPK2. (PMID:16343438)
• HIPK2 is an upstream protein kinase for Pax6 that may modulate Pax6-mediated transcriptional regulation (PMID:16407227)
• The homeodomain interacting protein kinase 2(HIPK2) overexpression, along with histone deacetylase-1, inhibited the cPLA2-luc promoter that is strongly acetylated in HIPK2i cells. (PMID:16467083)
• Degradation of endogenous HIPK2 depends on the presence of a functional p53 protein. (PMID:16601678)
• HIPK2 cooperates with p53 in Gal-3 repression and that this cooperation requires HIPK2 kinase activity. (PMID:16738336)
• Pc2 binds to and colocalizes with homeodomain interacting protein kinase 2 (HIPK2) and serves as a SUMO E3 ligase for this kinase. (PMID:17018294)
• Review summarizes recent findings from experimental HIPK2-guided gene expression programs that trigger differentiation and development or, alternatively, apoptosis. (PMID:17245128)
• HIPK2 is the IR-activated p53 Ser(46) kinase and is regulated by ATM. (PMID:17332358)
• These findings establish HIPK2 as an MDM2 target and support a model in which, upon nonsevere DNA damage, p53 represses its own phosphorylation at Ser46 due to HIPK2 degradation. (PMID:17349959)
• dysfunction of HIPK2 may play a role in the pathogenesis of leukemia (PMID:17533375)
• HIPK2-induced p53Ser46 phosphorylation activates the KILLER/DR5-mediated caspase-8 extrinsic apoptotic pathway. (PMID:17627287)
• HIPK2 and Cdc2 phosphorylate chromosomal high-mobility group A protein HMGA1 at the same site but show different site preferences. (PMID:17960875)
• the regulatory mechanisms by which HIPK2 is maintained at a low level, by WSB-1 in cells under normal conditions, and stabilized by genotoxic stresses. (PMID:18093972)
• HIPK2 is an important regulator of p53 activity in response to a chemotherapeutic drug. These results suggest that different drug-activated pathways may regulate HIPK2 and that HIPK2/p53Ser46 deregulation is involved in chemoresistance. (PMID:18395248)
• Frequent HIPK2 amplification and increased expression in pilocytic astrocytomas. (PMID:18408760)
• HIPK2 has a critical role in maintaining the transactivation activity of wtp53; low expression of HIPK2 may impair the p53 function in tumors harboring wtp53 (PMID:18483253)
• Results describe the control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR. (PMID:18536714)
• HIPK2 overexpression in tumor cells downregulated vascular endothelial growth factor mRNA levels and VEGF promoter activity. (PMID:18644116)
• the oncogenic protein PEBP2-beta-SMMHC prevents RUNX1/p300 phosphorylation by sequestering HIPK2 to mislocalized RUNX1/beta-SMMHC complexes (PMID:18695000)
• Fbx3 formed SCF(Fbx3) ubiquitin ligase and promoted the degradation of HIPK2 and p300 by the ubiquitin-proteasome pathway.PML inhibited this degradation. (PMID:18809579)
• Inhibition of MT2A expression by siRNA in the HIPK2 knockdown cells restored p53 transcription activity. (PMID:18996371)
• DNA damage-induced PML SUMOylation and are required for the ability of PML to cooperate with HIPK2 for the induction of cell death. (PMID:19015637)
• As HIPK2 has an important role as a negative regulator of gene expression, its elimination from promoter-associated repressor complexes allows the induction of a substantial fraction of hypoxia-induced genes. (PMID:19043406)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	hipk2	ENSDARG00000042518
mus_musculus	Hipk2	ENSMUSG00000061436
rattus_norvegicus	Hipk2	ENSRNOG00000007034
drosophila_melanogaster	mnb	FBGN0259168
caenorhabditis_elegans		WBGENE00003149
caenorhabditis_elegans		WBGENE00013727
caenorhabditis_elegans		WBGENE00185089

Paralogs (12): DYRK4 (ENSG00000010219), CLK1 (ENSG00000013441), DYRK1B (ENSG00000105204), HIPK3 (ENSG00000110422), CLK4 (ENSG00000113240), DYRK2 (ENSG00000127334), DYRK3 (ENSG00000143479), DYRK1A (ENSG00000157540), HIPK4 (ENSG00000160396), HIPK1 (ENSG00000163349), CLK2 (ENSG00000176444), CLK3 (ENSG00000179335)

Protein

Protein identifiers

Homeodomain-interacting protein kinase 2 — Q9H2X6 (reviewed: Q9H2X6)

All UniProt accessions (2): Q9H2X6, H7BXX9

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein kinase involved in transcription regulation, p53/TP53-mediated cellular apoptosis and regulation of the cell cycle. Acts as a corepressor of several transcription factors, including SMAD1 and POU4F1/Brn3a and probably NK homeodomain transcription factors. Phosphorylates PDX1, ATF1, PML, p53/TP53, CREB1, CTBP1, CBX4, RUNX1, EP300, CTNNB1, HMGA1, ZBTB4 and DAZAP2. Inhibits cell growth and promotes apoptosis through the activation of p53/TP53 both at the transcription level and at the protein level (by phosphorylation and indirect acetylation). The phosphorylation of p53/TP53 may be mediated by a p53/TP53-HIPK2-AXIN1 complex. Involved in the response to hypoxia by acting as a transcriptional co-suppressor of HIF1A. Mediates transcriptional activation of TP73. In response to TGFB, cooperates with DAXX to activate JNK. Negative regulator through phosphorylation and subsequent proteasomal degradation of CTNNB1 and the antiapoptotic factor CTBP1. In the Wnt/beta-catenin signaling pathway acts as an intermediate kinase between MAP3K7/TAK1 and NLK to promote the proteasomal degradation of MYB. Phosphorylates CBX4 upon DNA damage and promotes its E3 SUMO-protein ligase activity. Activates CREB1 and ATF1 transcription factors by phosphorylation in response to genotoxic stress. In response to DNA damage, stabilizes PML by phosphorylation. PML, HIPK2 and FBXO3 may act synergically to activate p53/TP53-dependent transactivation. Promotes angiogenesis, and is involved in erythroid differentiation, especially during fetal liver erythropoiesis. Phosphorylation of RUNX1 and EP300 stimulates EP300 transcription regulation activity. Triggers ZBTB4 protein degradation in response to DNA damage. In response to DNA damage, phosphorylates DAZAP2 which localizes DAZAP2 to the nucleus, reduces interaction of DAZAP2 with HIPK2 and prevents DAZAP2-dependent ubiquitination of HIPK2 by E3 ubiquitin-protein ligase SIAH1 and subsequent proteasomal degradation. Modulates HMGA1 DNA-binding affinity. In response to high glucose, triggers phosphorylation-mediated subnuclear localization shifting of PDX1. Involved in the regulation of eye size, lens formation and retinal lamination during late embryogenesis.

Subunit / interactions. Interacts with CREB1, SIAH1, WSB1, CBX4, TRADD, p53/TP53, TP73, TP63, CREBBP, DAXX, P53DINP1, SKI, SMAD1, SMAD2 and SMAD3, but not SMAD4. Interacts with ATF1, PML, RUNX1, EP300, NKX1-2, NKX2-5, UBE2I, HMGA1, CTBP1, AXIN1, NLK, MYB, POU4F1, POU4F2, POU4F3, UBE2I, UBL1 and ZBTB4. Probably part of a complex consisting of p53/TP53, HIPK2 and AXIN1. Interacts with SP100; positively regulates TP53-dependent transcription. Interacts with SUMO1P1/SUMO5. Interacts with DAZAP2; the interaction results in phosphorylation of DAZAP2 which causes localization of DAZAP2 to the nucleus, reduces interaction of DAZAP2 with HIPK2 and prevents DAZAP2-dependent degradation of HIPK2. Interacts with SIAH1; the interaction is promoted by DAZAP2 and results in SIAH1-mediated ubiquitination and subsequent proteasomal degradation of HIPK2. (Microbial infection) Interacts with Hantaan hantavirus nucleoprotein. (Microbial infection) Interacts with Seoul hantavirus nucleoprotein.

Subcellular location. Nucleus. PML body. Cytoplasm. Stress granule.

Tissue specificity. Highly expressed in heart, muscle and kidney. Weakly expressed in a ubiquitous way. Down-regulated in several thyroid and breast tumors.

Post-translational modifications. Autophosphorylation at Tyr-361 in the activation loop activates the kinase and promotes nuclear localization. Sumoylated. When conjugated it is directed to nuclear speckles. Desumoylated by SENP1. Sumoylation on Lys-32 is promoted by the E3 SUMO-protein ligase CBX4. Ubiquitinated by FBXO3, WSB1 and SIAH1, leading to rapid proteasome-dependent degradation. The degradation mediated by FBXO3, but not ubiquitination, is prevented in the presence of PML. The degradation mediated by WSB1 and SIAH1 is reversibly reduced upon DNA damage. Cleaved at Asp-923 and Asp-984 by CASP6 in a p53/TP53-dependent manner. The cleaved form lacks the autoinhibitory C-terminal domain (AID), resulting in a hyperactive kinase, which potentiates p53/TP53 Ser-46 phosphorylation and subsequent activation of the cell death machinery.

Induction. Unstable in unstressed cells but stabilized upon DNA damage. Induced by UV irradiation and other genotoxic agents (adriamycin ADR, cisplatin CDDP, etoposide, IR, roscovitin), thus triggering p53/TP53 apoptotic response. Consistutively negatively regulated by SIAH1 and WSB1 through proteasomal degradation. This negative regulation is impaired upon genotoxic stress. Repressed upon hypoxia (often associated with tumors), through MDM2- (an E3 ubiquitin ligases) mediated proteasomal degradation, thus inactivating p53/TP53 apoptotic response. This hypoxia repression is reversed by zinc. The stabilization mediated by DNA damage requires the damage checkpoint kinases ATM and ATR.

Miscellaneous. Interesting targets for cancer therapy. HIPK2 deregulation would end up in a multifactorial response leading to tumor chemoresistance by affecting p53/TP53 activity on one hand and to angiogenesis and cell proliferation by affecting HIF1A activity on the other hand. May provide important insights in the process of tumor progression, and may also serve as the crucial point in the diagnostic and therapeutical aspects of cancer. Tumor treatment may potential be improved by zinc supplementation in combination with chemotherapy to address hypoxia.

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

Isoforms (3)

UniProt ID	Names	Canonical?
Q9H2X6-1	1	yes
Q9H2X6-2	2
Q9H2X6-3	3

RefSeq proteins (2): NP_001106710, NP_073577* (*=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

Enzyme classification (BRENDA):

• EC 2.7.11.1 — non-specific serine/threonine protein kinase (BRENDA: 71 organisms, 682 substrates, 228 inhibitors, 23 Km, 6 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0007–0.64	11
KKRAARATSNVFA	0.013–0.045	3
PAH1 PHOSPHATIDATE PHOSPHATASE	0.0002	2
RRRLSSLRA	0.0036–0.0037	2
GTP	0.46	1
KKRAARASSNVFA	0.02	1
LYS-LYS-PHE-ASN-ARG-THR-LEU-SER-VAL-ALA	0.0093	1
MYELIN BASIC PROTEIN	0.145	1

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 (115 total): modified residue 21, helix 18, region of interest 16, sequence conflict 12, strand 11, mutagenesis site 11, cross-link 5, splice variant 4, turn 3, compositionally biased region 3, short sequence motif 2, binding site 2, site 2, sequence variant 2, chain 1, domain 1, active site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6P5S	X-RAY DIFFRACTION	2.19
7NCF	X-RAY DIFFRACTION	2.72

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H2X6-F1	53.39	0.27

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 (3): 324 (proton acceptor); 923–924 (cleavage; by casp6); 984–985 (cleavage; by casp6)

Ligand- & substrate-binding residues (2): 205–213; 228

Post-translational modifications (26): 16, 118, 135, 141, 252, 273, 361, 441, 482, 517, 566, 634, 668, 687, 815, 827, 934, 992, 1041, 1155 …

Mutagenesis-validated functional residues (11):

Position	Phenotype
228	locates in the nucleoplasm, no effect on interaction with ranbp9, but loss of kinase activity toward pml, runx1, ep300 a
228	abolishes enzymatic activity, no effect on interaction with tp53 and tp73 or on bmp-induced transcriptional activation.
359–361	enhances bmp-induced transcriptional activation; when associated with r-228.
803	impaired nuclear localization; when associated with a-805.
805	impaired nuclear localization; when associated with a-803.
833	impaired nuclear localization.
835	impaired nuclear localization.
885–892	loss of sumo and cbx4 interaction, and impaired nuclear and pml-nuclear bodies localization.
885–888	loss of sumo interaction, and impaired nuclear and pml-nuclear bodies localization.
892–895	loss of sumo interaction, and impaired nuclear and pml-nuclear bodies localization.
893–899	loss of sumo and cbx4 interaction, and impaired nuclear and pml-nuclear bodies localization.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-2032785	YAP1- and WWTR1 (TAZ)-stimulated gene expression
R-HSA-3899300	SUMOylation of transcription cofactors
R-HSA-5578768	Physiological factors
R-HSA-6804756	Regulation of TP53 Activity through Phosphorylation
R-HSA-8939243	RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known
R-HSA-9022692	Regulation of MECP2 expression and activity

MSigDB gene sets: 494 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, GCM_MAP4K4, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_IN_RESPONSE_TO_DNA_DAMAGE_BY_P53_CLASS_MEDIATOR, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, GOBP_RESPIRATORY_GASEOUS_EXCHANGE_BY_RESPIRATORY_SYSTEM, GOBP_BEHAVIOR, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_ADULT_BEHAVIOR, GOBP_PEPTIDYL_SERINE_MODIFICATION, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_ERYTHROCYTE_HOMEOSTASIS

GO Biological Process (42): negative regulation of transcription by RNA polymerase II (GO:0000122), eye development (GO:0001654), respiratory system process (GO:0003016), protein phosphorylation (GO:0006468), transforming growth factor beta receptor signaling pathway (GO:0007179), smoothened signaling pathway (GO:0007224), adult walking behavior (GO:0007628), cell population proliferation (GO:0008283), positive regulation of cell population proliferation (GO:0008284), anterior/posterior pattern specification (GO:0009952), gene expression (GO:0010467), retina layer formation (GO:0010842), peptidyl-serine phosphorylation (GO:0018105), neuron differentiation (GO:0030182), erythrocyte differentiation (GO:0030218), DNA damage response, signal transduction by p53 class mediator (GO:0030330), positive regulation of transforming growth factor beta receptor signaling pathway (GO:0030511), negative regulation of BMP signaling pathway (GO:0030514), PML body organization (GO:0030578), thyroid gland development (GO:0030878), epigenetic regulation of gene expression (GO:0040029), intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator (GO:0042771), negative regulation of neuron apoptotic process (GO:0043524), positive regulation of angiogenesis (GO:0045766), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of JNK cascade (GO:0046330), embryonic camera-type eye morphogenesis (GO:0048596), voluntary musculoskeletal movement (GO:0050882), neuron apoptotic process (GO:0051402), regulation of cell cycle (GO:0051726), embryonic retina morphogenesis in camera-type eye (GO:0060059), lens induction in camera-type eye (GO:0060235), SMAD protein signal transduction (GO:0060395), lung morphogenesis (GO:0060425), iris morphogenesis (GO:0061072), cellular response to hypoxia (GO:0071456), intrinsic apoptotic signaling pathway (GO:0097193), regulation of signal transduction by p53 class mediator (GO:1901796), negative regulation of ubiquitin-dependent protein catabolic process (GO:2000059), apoptotic process (GO:0006915)

GO Molecular Function (14): transcription coactivator activity (GO:0003713), transcription corepressor activity (GO:0003714), protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), protein tyrosine kinase activity (GO:0004713), ATP binding (GO:0005524), SMAD binding (GO:0046332), virion binding (GO:0046790), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (8): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytoplasmic stress granule (GO:0010494), nuclear body (GO:0016604), PML body (GO:0016605), RNA polymerase II transcription regulator complex (GO:0090575), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Generic Transcription Pathway	1
SUMO E3 ligases SUMOylate target proteins	1
Cardiac conduction	1
Regulation of TP53 Activity	1
Transcriptional regulation by RUNX1	1
Transcriptional Regulation by MECP2	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein kinase activity	3
negative regulation of DNA-templated transcription	2
transcription coregulator activity	2
protein binding	2
cellular anatomical structure	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
sensory organ development	1
visual system development	1
system process	1
respiratory gaseous exchange by respiratory system	1
phosphorylation	1
protein modification process	1
cellular response to transforming growth factor beta stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
cell surface receptor signaling pathway	1
adult locomotory behavior	1
walking behavior	1
cellular process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
regionalization	1
macromolecule biosynthetic process	1
neural retina development	1
anatomical structure formation involved in morphogenesis	1
retina morphogenesis in camera-type eye	1
protein phosphorylation	1
peptidyl-serine modification	1
cell differentiation	1
generation of neurons	1
myeloid cell differentiation	1
erythrocyte homeostasis	1
signal transduction in response to DNA damage	1
signal transduction by p53 class mediator	1
transforming growth factor beta receptor signaling pathway	1
regulation of transforming growth factor beta receptor signaling pathway	1
positive regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
positive regulation of cellular response to transforming growth factor beta stimulus	1
BMP signaling pathway	1

Protein interactions and networks

STRING

1654 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HIPK2	AXIN1	O15169	944
HIPK2	TP53	P04637	934
HIPK2	UBE2I	P50550	858
HIPK2	TP53INP1	Q96A56	847
HIPK2	CTBP1	Q13363	794
HIPK2	SIAH1	Q8IUQ4	742
HIPK2	SMAD2	Q15796	723
HIPK2	CREBBP	Q92793	703
HIPK2	DCAF7	P61962	692
HIPK2	SUMO1	P55856	690
HIPK2	SIAH2	O43255	689
HIPK2	MDM2	Q00987	681
HIPK2	PIAS2	O75928	676
HIPK2	WSB1	Q9Y6I7	667
HIPK2	CHMP5	Q9NZZ3	650

IntAct

68 interactions, top by confidence:

A	B	Type	Score
HIPK2	DCAF7	psi-mi:“MI:0915”(physical association)	0.730
DCAF7	HIPK2	psi-mi:“MI:0915”(physical association)	0.730
HIPK2	DCAF7	psi-mi:“MI:0407”(direct interaction)	0.730
DCAF7	HIPK2	psi-mi:“MI:0403”(colocalization)	0.730
UBE2I	HIPK2	psi-mi:“MI:0915”(physical association)	0.720
HIPK2	UBE2I	psi-mi:“MI:0915”(physical association)	0.720
HIPK2	TP53	psi-mi:“MI:0407”(direct interaction)	0.710
HIPK2	TP53	psi-mi:“MI:0915”(physical association)	0.710
MAP3K1	DCAF7	psi-mi:“MI:0914”(association)	0.710
DCAF7	MAP3K1	psi-mi:“MI:0403”(colocalization)	0.710
HIPK2	RUNX1	psi-mi:“MI:0915”(physical association)	0.640
HIPK2	RUNX1	psi-mi:“MI:0217”(phosphorylation reaction)	0.640
RUNX1	HIPK2	psi-mi:“MI:0915”(physical association)	0.640
HIPK2	MDM2	psi-mi:“MI:0915”(physical association)	0.620
MDM2	HIPK2	psi-mi:“MI:0915”(physical association)	0.620
HIPK2	MDM2	psi-mi:“MI:0217”(phosphorylation reaction)	0.620
HIPK2	EP300	psi-mi:“MI:0915”(physical association)	0.600
EP300	HIPK2	psi-mi:“MI:0217”(phosphorylation reaction)	0.600
EP300	HIPK2	psi-mi:“MI:0915”(physical association)	0.600

BioGRID (232): AATF (Affinity Capture-Western), HIPK2 (Affinity Capture-Western), AATF (Biochemical Activity), TP53 (Affinity Capture-Western), HIPK2 (Affinity Capture-Western), HIPK2 (Phenotypic Suppression), XAF1 (Affinity Capture-Western), HIPK2 (Biochemical Activity), HIPK2 (Reconstituted Complex), HIPK2 (Reconstituted Complex), HIPK2 (Reconstituted Complex), HIPK2 (Affinity Capture-Western), HIPK2 (Affinity Capture-MS), ABL1 (Affinity Capture-Western), ABL1 (Reconstituted Complex)

ESM2 similar proteins: A0AVK6, A4L9P5, B2GUN4, D2HNW6, D3ZGB1, E1BKK0, E1BP74, E1BZ85, F1LMN3, O14607, O15164, O15550, O70546, O88850, O88904, O94916, Q14B70, Q58CW6, Q58FA4, Q5RJA1, Q5ZKW8, Q64127, Q6B4Z3, Q7Z353, Q7Z3K3, Q84VX4, Q86Z02, Q8BJ34, Q8BZH4, Q8C7R7, Q8HWS3, Q8IXK0, Q8K0L9, Q8N187, Q93073, Q99743, Q99MQ1, Q99PP7, Q9BYH8, Q9ERH7

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

50 interactions.

A	Effect	B	Mechanism
HIPK2	down-regulates	CTBP1	phosphorylation
HIPK2	up-regulates	TP53	phosphorylation
HIPK2	down-regulates	HMGA1	phosphorylation
WSB1	down-regulates	HIPK2	ubiquitination
HIPK2	up-regulates	CREB1	phosphorylation
HIPK2	up-regulates	CDKN1B	phosphorylation
HIPK2	up-regulates	PML	phosphorylation
HIPK2	“up-regulates activity”	PAX6	phosphorylation
ABL1	“up-regulates activity”	HIPK2	phosphorylation
HIPK2	“up-regulates activity”	MECP2	phosphorylation
HIPK2	up-regulates	Apoptosis
FBXO3	“down-regulates quantity by destabilization”	HIPK2	binding
“Cullin 1-RBX1-Skp1”	“down-regulates quantity by destabilization”	HIPK2	polyubiquitination
SIAH1	“down-regulates quantity by destabilization”	HIPK2	polyubiquitination
HIPK2	“up-regulates activity”	HIPK2	phosphorylation
HIPK2	“down-regulates quantity by destabilization”	PPM1D	phosphorylation
HIPK2	“up-regulates activity”	CBX4	phosphorylation
SIAH1	“down-regulates quantity”	HIPK2	ubiquitination
HIPK2	“down-regulates quantity”	AATF	phosphorylation
HIPK2	“up-regulates activity”	EP300	phosphorylation
HIPK2	“up-regulates activity”	FOXM1	phosphorylation
SRC	“up-regulates activity”	HIPK2	phosphorylation
HIPK2	“down-regulates quantity”	BCHE	phosphorylation
HIPK2	“up-regulates activity”	CREBBP	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	35
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3980 predictions. Top by Δscore:

Variant	Effect	Δscore
7:139573395:AGCC:A	acceptor_loss	1.0000
7:139573398:C:CA	acceptor_loss	1.0000
7:139575123:CTTA:C	donor_loss	1.0000
7:139575124:TTACC:T	donor_loss	1.0000
7:139575125:TACC:T	donor_loss	1.0000
7:139575126:A:AC	donor_gain	1.0000
7:139575126:A:T	donor_loss	1.0000
7:139575126:AC:A	donor_gain	1.0000
7:139575127:C:CC	donor_gain	1.0000
7:139575127:CC:C	donor_gain	1.0000
7:139575127:CCTG:C	donor_gain	1.0000
7:139575127:CCTGG:C	donor_gain	1.0000
7:139575284:GTTGA:G	acceptor_gain	1.0000
7:139575285:TTGA:T	acceptor_gain	1.0000
7:139575285:TTGAC:T	acceptor_gain	1.0000
7:139575286:TGA:T	acceptor_gain	1.0000
7:139575286:TGAC:T	acceptor_loss	1.0000
7:139575286:TGACT:T	acceptor_gain	1.0000
7:139575287:GA:G	acceptor_gain	1.0000
7:139575287:GACTG:G	acceptor_gain	1.0000
7:139575288:ACTGT:A	acceptor_gain	1.0000
7:139575289:C:CC	acceptor_gain	1.0000
7:139575289:CTGTG:C	acceptor_gain	1.0000
7:139575290:T:A	acceptor_gain	1.0000
7:139575290:T:G	acceptor_loss	1.0000
7:139575291:G:C	acceptor_gain	1.0000
7:139575291:G:GC	acceptor_gain	1.0000
7:139575295:C:CT	acceptor_gain	1.0000
7:139575296:G:T	acceptor_gain	1.0000
7:139583837:TC:T	donor_gain	1.0000

AlphaMissense

7863 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:139626697:A:G	L508P	1.000
7:139626730:C:G	R497P	1.000
7:139631176:A:G	W446R	1.000
7:139631176:A:T	W446R	1.000
7:139631208:A:G	F435S	1.000
7:139631210:A:C	F434L	1.000
7:139631210:A:T	F434L	1.000
7:139631211:A:G	F434S	1.000
7:139631212:A:G	F434L	1.000
7:139631230:C:A	G428W	1.000
7:139631238:A:G	L425S	1.000
7:139631280:C:G	R411P	1.000
7:139631637:A:G	W398R	1.000
7:139631637:A:T	W398R	1.000
7:139631666:C:T	G388D	1.000
7:139631667:C:G	G388R	1.000
7:139631674:C:A	W385C	1.000
7:139631674:C:G	W385C	1.000
7:139631676:A:G	W385R	1.000
7:139631676:A:T	W385R	1.000
7:139631708:A:G	L374P	1.000
7:139631720:G:T	P370H	1.000
7:139715932:C:A	R368M	1.000
7:139715982:G:C	S351R	1.000
7:139715982:G:T	S351R	1.000
7:139715984:T:G	S351R	1.000
7:139715986:G:T	A350D	1.000
7:139715992:C:T	G348D	1.000
7:139715993:C:G	G348R	1.000
7:139715994:A:C	F347L	1.000

dbSNP variants (sampled 300 via entrez): RS1000008063 (7:139726430 C>G), RS1000009076 (7:139732843 G>A), RS1000042714 (7:139726017 G>A,C), RS1000047503 (7:139687090 G>A), RS1000060040 (7:139648374 G>T), RS1000070405 (7:139565218 T>C), RS1000084744 (7:139714021 C>T), RS1000093659 (7:139732628 T>C), RS1000099090 (7:139744368 A>C), RS1000101259 (7:139619622 G>A), RS1000110594 (7:139773802 G>T), RS1000132925 (7:139571434 A>G), RS1000135168 (7:139692739 C>A,T), RS1000135762 (7:139631529 A>G), RS1000174899 (7:139761891 A>C)

Disease associations

OMIM: gene MIM:606868 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003445_11	Response to cyclophosphamide in systemic lupus erythematosus with lupus nephritis	6.000000e-06
GCST004279_1	Systolic blood pressure	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4576 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

30 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 263,501 (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
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL1983268	ENTRECTINIB	4	3,510
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3301610	ABEMACICLIB	4	7,045
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL223360	LINIFANIB	3	3,925
CHEMBL300138	ENZASTAURIN	3	3,209
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL91829	RUBOXISTAURIN	3	77
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL1721885	SU-014813	2	363
CHEMBL1967878	CENISERTIB	2	358
CHEMBL1980297	ILORASERTIB	2	581
CHEMBL215152	DEFOSBARASERTIB	2	372
CHEMBL475251	R-406	2
CHEMBL513909	BI-2536	2
CHEMBL521851	PICTILISIB	2
CHEMBL1084546	PF-00562271	1
CHEMBL1908397	KW-2449	1
CHEMBL296468	BMS-387032	1
CHEMBL482967	CYC-116	1
CHEMBL494089	GSK-690693	1
CHEMBL5426285	5-(6-BENZOTHIAZOLYLMETHYLENE)-3,5-DIHYDRO-2-(((1S)-1-(METHOXYMETHYL)-3-METHYLBUTYL)AMINO)-4H-IMIDAZOL-4-ONE, (5Z)-	1
CHEMBL574738	AST-487	1

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — HIPK subfamily

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
compound 5b [PMID: 24900464]	Inhibition	8.52	pIC50
compound 1a [PMID: 24900749]	Inhibition	7.4	pIC50

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
Furan thiazolidinediones, A64	KD	9.5 nM

ChEMBL bioactivities

395 potent at pChembl≥5 of 395 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.40	Ki	3.981	nM	CHEMBL1997554
8.30	IC50	5	nM	CHEMBL4750420
8.20	Ki	6.31	nM	CHEMBL1983932
8.20	Ki	6.31	nM	CHEMBL243518
8.20	Ki	6.31	nM	CHEMBL243298
8.20	Ki	6.31	nM	CHEMBL1987448
8.20	Ki	6.31	nM	CHEMBL385478
8.14	Kd	7.3	nM	AST-487
8.10	Ki	7.943	nM	CHEMBL1967662
8.10	Ki	7.943	nM	CHEMBL1999931
8.00	Ki	10	nM	CHEMBL1996980
7.90	Ki	12.59	nM	CHEMBL1992363
7.90	Ki	12.59	nM	CHEMBL396523
7.90	Ki	12.59	nM	CHEMBL2003637
7.82	IC50	15	nM	CHEMBL4743939
7.80	Ki	15.85	nM	CHEMBL1966628
7.80	Ki	15.85	nM	CHEMBL1964288
7.80	Ki	15.85	nM	CHEMBL213207
7.70	IC50	20	nM	CHEMBL2062565
7.70	Ki	19.95	nM	CHEMBL1997643
7.70	Ki	19.95	nM	CHEMBL1974250
7.70	Ki	19.95	nM	CHEMBL1999153
7.70	Ki	19.95	nM	CHEMBL1241473
7.64	IC50	23	nM	CHEMBL4754195
7.60	Ki	25.12	nM	CHEMBL1970821
7.60	Ki	25.12	nM	CHEMBL2005509
7.60	Ki	25.12	nM	CHEMBL1995813
7.60	Ki	25.12	nM	CHEMBL244378
7.60	Ki	25.12	nM	CHEMBL1965660
7.60	Ki	25.12	nM	CHEMBL1972290
7.60	Ki	25.12	nM	CHEMBL1991078
7.60	Ki	25.12	nM	CHEMBL1966204
7.55	IC50	28	nM	CHEMBL4790791
7.54	IC50	29	nM	CHEMBL4754195
7.52	IC50	30	nM	CHEMBL2062563
7.52	IC50	30	nM	CHEMBL3937369
7.52	IC50	30	nM	CHEMBL4762964
7.51	IC50	31	nM	ABEMACICLIB
7.51	Kd	31	nM	SUNITINIB
7.50	Ki	31.62	nM	CHEMBL2003638
7.50	Ki	31.62	nM	CHEMBL1980435
7.50	Ki	31.62	nM	CHEMBL1986943
7.50	Ki	31.62	nM	CHEMBL1982400
7.50	Ki	31.62	nM	CHEMBL1982271
7.50	Ki	31.62	nM	CHEMBL379975
7.50	Ki	31.62	nM	CHEMBL1992220
7.40	IC50	40	nM	CHEMBL2409175
7.40	IC50	40	nM	CHEMBL3103192
7.40	Ki	39.81	nM	CHEMBL1986263
7.40	Ki	39.81	nM	CHEMBL2005718

PubChem BioAssay actives

83 with measured affinity, of 1525 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-[6-[6-(propan-2-ylamino)indazol-1-yl]pyrazin-2-yl]benzoic acid	1391115: Inhibition of HIPK2 (unknown origin)	ic50	0.0030	uM
N-[3-[3-cyano-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-yl]-1H-indol-5-yl]acetamide	673774: Inhibition of HipK2	ic50	0.0030	uM
N-[1-[3-cyano-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-yl]indol-6-yl]-N-methylacetamide	673774: Inhibition of HipK2	ic50	0.0030	uM
3-naphthalen-2-yl-5-(1H-pyrazol-4-yl)furo[3,2-b]pyridine	1733095: Inhibition of human recombinant HIPK2 using myelin substrate by radiometric scintillation assay	ic50	0.0050	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	625129: Binding constant for HIPK2 kinase domain	kd	0.0073	uM
3-(4-methoxyphenyl)-5-(1H-pyrazol-4-yl)furo[3,2-b]pyridine	1733095: Inhibition of human recombinant HIPK2 using myelin substrate by radiometric scintillation assay	ic50	0.0150	uM
N-[1-[3-cyano-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-yl]pyrrolo[3,2-b]pyridin-6-yl]acetamide	673774: Inhibition of HipK2	ic50	0.0200	uM
3-(1-methylpyrazol-4-yl)-5-(1H-pyrazol-4-yl)furo[3,2-b]pyridine	1733095: Inhibition of human recombinant HIPK2 using myelin substrate by radiometric scintillation assay	ic50	0.0280	uM
5-(1-methylpyrazol-4-yl)-3-(3-pyridin-4-ylphenyl)furo[3,2-b]pyridine	1722639: Inhibition of human HIPK2 by radiometric assay	ic50	0.0290	uM
6-imidazo[4,5-b]pyridin-1-yl-N-[5-(2-piperidin-1-ylethoxy)-2-pyridinyl]pyrimidin-4-amine	1533154: Inhibition recombinant human HIPK2 (165 to 564 residues) after 5 mins in presence of [33P] ATP by Topcount method	ic50	0.0300	uM
5-(1-methylpyrazol-4-yl)-3-[3-(1H-pyrazol-5-yl)phenyl]furo[3,2-b]pyridine	1733095: Inhibition of human recombinant HIPK2 using myelin substrate by radiometric scintillation assay	ic50	0.0300	uM
N-[1-[3-cyano-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-yl]indol-6-yl]acetamide	673774: Inhibition of HipK2	ic50	0.0300	uM
Abemaciclib	2171308: Inhibition of recombinant human N-terminal His6-tagged HIPK2 (165 to 564 residues) expressed in baculovirus infected Sf21 insect cells using MBP as substrate	ic50	0.0310	uM
Sunitinib	507970: Binding affinity to HIPK2	kd	0.0310	uM
N-[2-[2-aminoethyl(methyl)amino]-5-[[3-cyano-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-yl]amino]phenyl]acetamide	1301613: Inhibition of Hipk2 (unknown origin) by quantitative PCR	ic50	0.0400	uM
N-[5-[[3-cyano-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-yl]amino]-2-methylphenyl]acetamide	760572: Inhibition of Hipk-2 (unknown origin)	ic50	0.0400	uM
3-(4-prop-1-en-2-ylphenyl)-5-(1H-pyrazol-4-yl)furo[3,2-b]pyridine	1733095: Inhibition of human recombinant HIPK2 using myelin substrate by radiometric scintillation assay	ic50	0.0410	uM
3-phenyl-5-(1H-pyrazol-4-yl)furo[3,2-b]pyridine	1733095: Inhibition of human recombinant HIPK2 using myelin substrate by radiometric scintillation assay	ic50	0.0420	uM
N-[1-[3-cyano-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-yl]indazol-6-yl]acetamide	673774: Inhibition of HipK2	ic50	0.0500	uM
N-[1-[3-cyano-7-[3-(dimethylamino)propylamino]pyrazolo[1,5-a]pyrimidin-5-yl]indol-6-yl]acetamide	673774: Inhibition of HipK2	ic50	0.0600	uM
3-[4-(1-methylcyclopropyl)phenyl]-5-(1H-pyrazol-4-yl)furo[3,2-b]pyridine	1733095: Inhibition of human recombinant HIPK2 using myelin substrate by radiometric scintillation assay	ic50	0.0680	uM
5-(1-methylpyrazol-4-yl)-3-[3-(1-methylpyrazol-4-yl)phenyl]furo[3,2-b]pyridine	1733095: Inhibition of human recombinant HIPK2 using myelin substrate by radiometric scintillation assay	ic50	0.0700	uM
(5E)-5-[[6-oxo-5-(6-piperazin-1-yl-3-pyridinyl)-1H-pyridin-3-yl]methylidene]-1,3-thiazolidine-2,4-dione	1733110: Inhibition of HIPK2 (unknown origin) by selectscreen kinase assay	ic50	0.0740	uM
(5E)-2-amino-5-[[6-oxo-5-(6-piperazin-1-yl-3-pyridinyl)-1H-pyridin-3-yl]methylidene]-1,3-thiazol-4-one	1799557: Biochemical Assay from Article 10.1016/j.chembiol.2011.05.010: “High-throughput kinase profiling: a more efficient approach toward the discovery of new kinase inhibitors.”	ic50	0.0740	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	625129: Binding constant for HIPK2 kinase domain	kd	0.0920	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	1733112: Inhibition of HIPK2 (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	1733112: Inhibition of HIPK2 (unknown origin)	ic50	0.1000	uM
Sorafenib	1733112: Inhibition of HIPK2 (unknown origin)	ic50	0.1000	uM
1-N’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	1733112: Inhibition of HIPK2 (unknown origin)	ic50	0.1000	uM
5-(1-methylpyrazol-4-yl)-3-[3-(1H-pyrazol-4-yl)phenyl]furo[3,2-b]pyridine	1733095: Inhibition of human recombinant HIPK2 using myelin substrate by radiometric scintillation assay	ic50	0.1020	uM
3-(4-tert-butylphenyl)-5-(1H-pyrazol-4-yl)furo[3,2-b]pyridine	1733095: Inhibition of human recombinant HIPK2 using myelin substrate by radiometric scintillation assay	ic50	0.1190	uM
3-(4-tert-butylphenyl)-5-(2H-triazol-4-yl)furo[3,2-b]pyridine	1733095: Inhibition of human recombinant HIPK2 using myelin substrate by radiometric scintillation assay	ic50	0.1230	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	1715323: Inhibition of human HIPK2 using MBP as substrate by [gamma-33P]-ATP assay	ic50	0.1460	uM
3-(4-phenylphenyl)-5-(1H-pyrazol-4-yl)furo[3,2-b]pyridine	1733095: Inhibition of human recombinant HIPK2 using myelin substrate by radiometric scintillation assay	ic50	0.1720	uM
5-(1-methylpyrazol-4-yl)-3-(3-piperidin-4-ylphenyl)furo[3,2-b]pyridine	1733095: Inhibition of human recombinant HIPK2 using myelin substrate by radiometric scintillation assay	ic50	0.1790	uM
(2S)-1-[[5-(3-methyl-2H-indazol-5-yl)-3-pyridinyl]oxy]-3-phenylpropan-2-amine	625129: Binding constant for HIPK2 kinase domain	kd	0.2200	uM
3-[3-(1-methylpiperidin-4-yl)phenyl]-5-(1-methylpyrazol-4-yl)furo[3,2-b]pyridine	1733095: Inhibition of human recombinant HIPK2 using myelin substrate by radiometric scintillation assay	ic50	0.2600	uM
3-(6-morpholin-4-yl-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl)phenol	625129: Binding constant for HIPK2 kinase domain	kd	0.2900	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	625129: Binding constant for HIPK2 kinase domain	kd	0.3000	uM
(5Z)-5-(1,3-benzothiazol-6-ylmethylidene)-2-[(2R)-1-methoxy-4-methylpentan-2-yl]iminoimidazolidin-4-one	2024507: Inhibition of human HIPK2 assessed as remaining activity by eurofins-cerep kinase profiler analysis	ic50	0.3170	uM
4,5,6,7-tetrabromo-2-(1H-imidazol-2-yl)isoindole-1,3-dione	1733109: Inhibition of human HIPK2 using NKRRRSPTPPE as substrate preincubated for 10 mins followed by substrate and [33P-ATP] addition by scintillation counting method	ic50	0.3300	uM
2-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol	625129: Binding constant for HIPK2 kinase domain	kd	0.3500	uM
3-(4-tert-butylphenyl)-5-(2H-tetrazol-5-yl)furo[3,2-b]pyridine	1733095: Inhibition of human recombinant HIPK2 using myelin substrate by radiometric scintillation assay	ic50	0.3570	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	507970: Binding affinity to HIPK2	kd	0.3700	uM
4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-[[(3S)-piperidin-3-yl]methoxy]imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol	625129: Binding constant for HIPK2 kinase domain	kd	0.3900	uM
3-(4-benzylphenyl)-5-(1H-pyrazol-4-yl)furo[3,2-b]pyridine	1733095: Inhibition of human recombinant HIPK2 using myelin substrate by radiometric scintillation assay	ic50	0.4840	uM
4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one	625129: Binding constant for HIPK2 kinase domain	kd	0.5000	uM
3-[4-(2-methylpropyl)phenyl]-5-(1H-pyrazol-4-yl)furo[3,2-b]pyridine	1733095: Inhibition of human recombinant HIPK2 using myelin substrate by radiometric scintillation assay	ic50	0.5010	uM
4-[2-(1H-indazol-4-yl)-6-[(4-methylsulfonylpiperazin-1-yl)methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine	625129: Binding constant for HIPK2 kinase domain	kd	0.5200	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	1526321: Binding affinity to recombinant full-length N-terminal His-FLAG-tagged HIPK2 (unknown origin) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.5590	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	decreases expression, increases expression, increases reaction, affects cotreatment	6
bisphenol A	increases expression, affects cotreatment, decreases expression, decreases methylation	3
sodium arsenite	affects localization, increases stability, increases phosphorylation, affects expression, increases expression	3
Doxorubicin	affects binding, increases phosphorylation, decreases reaction, increases reaction, increases activity (+3 more)	3
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
cobaltous chloride	decreases degradation, affects binding, increases expression, decreases response to substance, decreases expression (+4 more)	2
Cadmium	increases abundance, increases expression, decreases expression	2
Progesterone	affects cotreatment, decreases expression	2
Tetrachlorodibenzodioxin	decreases reaction, increases expression, affects expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Tretinoin	increases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
Particulate Matter	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
TAK-243	increases sumoylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
sodium arsenate	increases abundance, increases expression	1
trichostatin A	decreases expression	1
2-butenal	decreases expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
zinc chloride	affects binding, decreases reaction, increases reaction, decreases expression	1
butyraldehyde	decreases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	increases expression	1
manganese chloride	decreases expression, increases abundance	1
benzo(e)pyrene	decreases methylation	1

ChEMBL screening assays

317 unique, capped per target: 316 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1004131	Binding	Inhibition of HIPK2 at 1 uM relative to control	Novel potent BRAF inhibitors: toward 1 nM compounds through optimization of the central phenyl ring. — J Med Chem
CHEMBL1963754	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: HIPK2	PubChem BioAssay data set

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SR44	HAP1 HIPK2 (-) 1	Cancer cell line	Male
CVCL_SR45	HAP1 HIPK2 (-) 2	Cancer cell line	Male
CVCL_SR46	HAP1 HIPK2 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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