HDAC4

Summary

HDAC4 (histone deacetylase 4, HGNC:14063) is a protein-coding gene on chromosome 2q37.3, encoding Histone deacetylase 4 (P56524). Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4).

Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromosome structure and affects transcription factor access to DNA. The protein encoded by this gene belongs to class II of the histone deacetylase/acuc/apha family. It possesses histone deacetylase activity and represses transcription when tethered to a promoter. This protein does not bind DNA directly, but through transcription factors MEF2C and MEF2D. It seems to interact in a multiprotein complex with RbAp48 and HDAC3.

Source: NCBI Gene 9759 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with central hypotonia and dysmorphic facies (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 24
• Clinical variants (ClinVar): 754 total — 7 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 113
• Druggable target: yes — 31 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• Transcription factor: yes — 24 downstream targets (CollecTRI)
• MANE Select transcript: NM_001378414

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14063
Approved symbol	HDAC4
Name	histone deacetylase 4
Location	2q37.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0288, HDAC-A, HDACA, HD4, HA6116, HDAC-4
Ensembl gene	ENSG00000068024
Ensembl biotype	protein_coding
OMIM	605314
Entrez	9759

Gene structure

Transcript identifiers

Ensembl transcripts: 35 — 23 protein_coding, 9 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000345617, ENST00000430200, ENST00000445704, ENST00000446876, ENST00000454542, ENST00000460235, ENST00000461113, ENST00000463007, ENST00000487617, ENST00000493582, ENST00000494800, ENST00000495497, ENST00000496347, ENST00000535493, ENST00000543185, ENST00000553145, ENST00000685474, ENST00000690129, ENST00000896768, ENST00000896769, ENST00000896770, ENST00000896771, ENST00000913662, ENST00000913663, ENST00000913664, ENST00000913665, ENST00000913666, ENST00000913667, ENST00000913668, ENST00000913669, ENST00000913670, ENST00000913671, ENST00000913672, ENST00000913673, ENST00000971555

RefSeq mRNA: 8 — MANE Select: NM_001378414 NM_001378414, NM_001378415, NM_001378416, NM_001378417, NM_001435991, NM_001435992, NM_001435993, NM_006037

CCDS: CCDS2529, CCDS92981

Canonical transcript exons

ENST00000543185 — 27 exons

Exon	Start	End
ENSE00001207161	239048168	239053136
ENSE00001769744	239400978	239401020
ENSE00002234229	239053460	239053601
ENSE00002235788	239054749	239054833
ENSE00002355012	239081095	239081192
ENSE00003472216	239176413	239176563
ENSE00003474127	239144583	239144714
ENSE00003478786	239082102	239082221
ENSE00003489224	239084155	239084242
ENSE00003503479	239066722	239066855
ENSE00003513008	239134527	239134643
ENSE00003513997	239111526	239111712
ENSE00003533601	239102776	239102896
ENSE00003570623	239115053	239115310
ENSE00003581402	239163803	239163923
ENSE00003592402	239068489	239068607
ENSE00003600210	239087559	239087614
ENSE00003617620	239156652	239156773
ENSE00003620044	239095010	239095056
ENSE00003638846	239090009	239090116
ENSE00003647368	239139684	239139796
ENSE00003648118	239126456	239126694
ENSE00003659375	239108050	239108183
ENSE00003664840	239352678	239352918
ENSE00003684778	239236593	239236664
ENSE00003687180	239189833	239190077
ENSE00003741725	239134245	239134443

Expression profiles

Bgee: expression breadth ubiquitous, 277 present calls, max score 97.64.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.3329 / max 131.9363, expressed in 1695 samples.

FANTOM5 promoters (15 alternative TSS)

Promoter ID	TPM avg	Samples expressed
34811	4.2140	1553
34812	1.1318	701
34810	0.5402	306
34804	0.5279	183
34809	0.2401	119
34800	0.1406	49
34801	0.1360	54
34803	0.0959	49
34799	0.0907	42
34802	0.0842	42

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	97.64	gold quality
gluteal muscle	UBERON:0002000	97.06	gold quality
gastrocnemius	UBERON:0001388	94.14	gold quality
muscle of leg	UBERON:0001383	93.16	gold quality
tibialis anterior	UBERON:0001385	91.47	gold quality
hindlimb stylopod muscle	UBERON:0004252	91.25	gold quality
muscle organ	UBERON:0001630	91.14	gold quality
muscle layer of sigmoid colon	UBERON:0035805	90.79	gold quality
endothelial cell	CL:0000115	90.75	gold quality
deltoid	UBERON:0001476	89.81	silver quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	89.28	gold quality
blood	UBERON:0000178	88.51	gold quality
biceps brachii	UBERON:0001507	87.83	gold quality
sigmoid colon	UBERON:0001159	87.23	gold quality
skeletal muscle tissue	UBERON:0001134	86.76	gold quality
lower esophagus	UBERON:0013473	86.72	gold quality
lower esophagus muscularis layer	UBERON:0035833	86.71	gold quality
periodontal ligament	UBERON:0008266	86.55	gold quality
quadriceps femoris	UBERON:0001377	86.50	gold quality
colonic epithelium	UBERON:0000397	86.02	gold quality
Brodmann (1909) area 23	UBERON:0013554	85.88	gold quality
germinal epithelium of ovary	UBERON:0001304	85.83	gold quality
vastus lateralis	UBERON:0001379	85.69	gold quality
bone marrow cell	CL:0002092	85.12	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	85.11	gold quality
primary visual cortex	UBERON:0002436	84.82	gold quality
middle temporal gyrus	UBERON:0002771	84.66	gold quality
left testis	UBERON:0004533	84.41	gold quality
gingival epithelium	UBERON:0001949	83.78	gold quality
right testis	UBERON:0004534	83.73	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-119	yes	27.96
E-ANND-3	yes	6.75

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

24 targets.

Target	Regulation
ATF4	Unknown
CA9	Unknown
CDKN1A	Repression
CDKN2A	Repression
HDAC3	Unknown
HOXB13	Repression
IL10	Repression
IL5	Unknown
JUN	Activation
KLF4	Unknown
MEF2A	Repression
MMP13	Repression
PTGES	Unknown
PTGS2	Activation
PTPA	Unknown
RECK	Unknown
RUNX2	Repression
SLC2A4	Unknown
SMAD4	Unknown
TGIF1	Activation
TGIF2	Activation
VCAM1	Activation
VEGFA	Repression
WT1	Repression

Upstream regulators (CollecTRI, top): SP1, SP3

miRNA regulators (miRDB)

214 targeting HDAC4, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-12121	99.99	66.64	255
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-4666A-3P	99.96	71.71	3434

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• HDAC4 is primarily a cytoplasmic resident protein, requiring a trans-acting nuclear localization signal for nuclear localization. (PMID:11792813)
• The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase (PMID:12032081)
• MITR, HDAC4, and HDAC5 associate with heterochromatin protein 1 (HP1), an adaptor protein that recognizes methylated lysines within histone tails and mediates transcriptional repression by recruiting histone methyltransferase (PMID:12242305)
• This protein interacts with 53BP1 to mediate DNA damage response. (PMID:12668657)
• full-length HDAC4 can repress MEF2 through multiple independent repressive domains (PMID:12709441)
• the zinc fingers of nuclear receptors provide a general interaction interface for HDACs 3 and 4, recruiting HDACs 3 and 4 to the target DNA causing demonstrable histone deacetylation (PMID:12943985)
• caspases could specifically modulate gene repression and apoptosis through the proteolyic processing of HDAC4 (PMID:15075374)
• ICP0 of herpes simplex virus type 1 interacts with and controls the repressor activity of class II HDAC4 (PMID:15194749)
• HDAC4 has a role in cell death and differentiation (PMID:15205465)
• data indicate that recruitment of HDAC4 is necessary for PLZF-mediated repression in both normal and leukaemic cells (PMID:15467736)
• HDAC4 regulates ERalpha activity as a N-terminal coregulator. (PMID:16051668)
• histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications regulate MEF2 (PMID:16166628)
• Results show that calcium/calmodulin-dependent kinase II (CaMKII) signals specifically to histone deacetylase (HDAC)4 by binding to a unique docking site that is absent in other class IIa HDACs. (PMID:16767219)
• HDAC4 (histone deacetylase 4) and p300, a known HAT (histone acetyltransferase), reversibly controlled the activity of the IL-5 promoter in vivo and in vitro, with a concurrent alteration of histone H3 acetylation status at the promoter regions. (PMID:16922677)
• HDAC4 as a specific downstream substrate of CaMKIIdeltaB in cardiac cells and have broad applications for the signaling pathways leading to cardiac hypertrophy and heart failure. (PMID:17179159)
• crystallographic analysis of the N-terminal domain of histone deacetylase 4 (PMID:17360518)
• Results show that both JARID1B and HDAC4 expressed in breast cancers. (PMID:17373667)
• expression of the silencing mediator of retinoid and thyroid receptor (SMRT) & histone deacetylase4 (HDAC4) enhances formation of Bach2 foci in nuclear matrix. SMRT mediates HDAC4 binding to Bach2, & HDAC4 facilitates retention of Bach2 in the foci. (PMID:17383980)
• HDAC4 is an essential epigenetic regulator of MF differentiation and HDAC4 is a potential target for treating MF-related disorders. (PMID:17610967)
• Data suggest that, through specific posttranslation modifications, extracellular signals control two distinct nuclear pools of HDAC4 to differentially dictate cell death and differentiation. (PMID:17636017)
• Results show that recruitment of histone deacetylase 4 is involves the CRIF1-mediated inhibition of AR transactivation. (PMID:17885209)
• NO-dependent PP2A activation plays a key role in nuclear translocation of class II HDACs HDAC4 and HDAC5 (PMID:17975112)
• These observations suggest that PP2A, via the dephosphorylation of multiple serines including the 14-3-3 binding sites and serine 298, controls HDAC4 nuclear import. (PMID:18045992)
• These findings revealed that TNF-alpha induced VCAM-1 expression via multiple signaling pathways. (PMID:18227124)
• Structural and functional analysis of the human HDAC4 catalytic domain reveals a regulatory structural zinc-binding domain (PMID:18614528)
• HDAC4 is a novel regulator of colon cell proliferation through repression of p21 (PMID:18632985)
• This study showed that in skeletal muscle, HDAC4 is a critical modulator of MEF2-dependent structural and contractile gene expression in response to neural activity. (PMID:18780762)
• HDAC4 interacts with Sp1, binds and reduces histone H3 acetylation at the Sp1/Sp3 binding site-rich p21(WAF1/Cip1) proximal promoter, suggesting a key role for Sp1 in HDAC4-mediated repression of p21(WAF1/Cip1). (PMID:18850004)
• MELOE-1 is a new antigen overexpressed in melanomas and involved in adoptive T cell transfer efficiency. (PMID:18936238)
• Analysis of a series of HDAC4 mutants by nuclear import assay suggested that phosphorylation and subsequent 14-3-3 binding reduce nuclear import rather than enhancing nuclear export. (PMID:18952052)
• P/CAF deacetylation by HDAC3 and in a minor degree by HDAC1, HDAC2, or HDAC4 leads to cytoplasmic accumulation of P/CAF. (PMID:19015268)
• These results indicate that HDAC4 and HDAC5 increase the transactivation function of HIF-1alpha by promoting dissociation of HIF-1alpha from FIH-1 and association with p300. (PMID:19071119)
• HDAC4 contributes to transcriptional induction of mPGES-1 by IL-1 through a mechanism involving up-regulation of Egr-1 transcriptional activity (PMID:19115247)
• recent developments in the crystal structure analysis of human HDAC4, HDAC7, and HDAC8 [REVIEW] (PMID:19355988)
• reduced expression of HDAC4 in chondrosarcoma cells increases expression of Runx2 leading to increased expression of VEGF and in vitro angiogenesis (PMID:19509297)
• These data demonstrate that the differentiation of normal human lung fibroblasts to myofibroblasts is HDAC4 dependent and requires phosphorylation of Akt. (PMID:19700647)
• show that HDAC4 overexpression promotes TGF-beta1-induced synovium-derived stem cells chondrogenesis but inhibits chondrogenically differentiated stem cell hypertrophy. (PMID:19716643)
• apicidin acts as an effective anti-tumor agent on human endometrial cancer cells by regulating cell proliferation and apoptosis through the down-regulation of HDAC3 and HDAC4 (PMID:19956841)
• HDAC4 represses matrix metalloproteinase-13 transcription in osteoblastic cells, and parathyroid hormone controls this repression (PMID:20097749)
• JNK-ATF-2 inhibits thrombomodulin (TM) expression by recruiting histone deacetylase4 (HDAC4) and forming a transcriptional repression complex in the TM promoter. (PMID:20116378)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	hdac4	ENSDARG00000098349
mus_musculus	Hdac4	ENSMUSG00000026313
rattus_norvegicus	Hdac4	ENSRNOG00000020372
caenorhabditis_elegans		WBGENE00009657
caenorhabditis_elegans		WBGENE00009663
caenorhabditis_elegans		WBGENE00219378

Paralogs (10): HDAC9 (ENSG00000048052), HDAC7 (ENSG00000061273), HDAC6 (ENSG00000094631), HDAC10 (ENSG00000100429), HDAC5 (ENSG00000108840), HDAC1 (ENSG00000116478), HDAC8 (ENSG00000147099), HDAC11 (ENSG00000163517), HDAC3 (ENSG00000171720), HDAC2 (ENSG00000196591)

Protein

Protein identifiers

Histone deacetylase 4 — P56524 (reviewed: P56524)

All UniProt accessions (6): P56524, A0A7I2SVS4, C9J0X4, C9J481, H7BZT3, H7C397

UniProt curated annotations — full annotation on UniProt →

Function. Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation via its interaction with the myocyte enhancer factors such as MEF2A, MEF2C and MEF2D. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer. Deacetylates HSPA1A and HSPA1B at ‘Lys-77’ leading to their preferential binding to co-chaperone STUB1.

Subunit / interactions. Homodimer. Homodimerization via its N-terminal domain. Interacts with MEF2A. Interacts with MEF2C and MEF2D. Interacts with AHRR. Interacts with NR2C1. Interacts with HDAC7. Interacts with a 14-3-3 chaperone proteins in a phosphorylation dependent manner. Interacts with 14-3-3 protein YWHAB. Interacts with BTBD14B. Interacts with KDM5B. Interacts with MYOCD. Interacts with MORC2. Interacts (via PxLPxI/L motif) with ANKRA2 (via ankyrin repeats). Interacts with CUL7 (as part of the 3M complex); negatively regulated by ANKRA2. Interacts with EP300 in the presence of TFAP2C. Interacts with HSPA1A and HSPA1B leading to their deacetylation at ‘Lys-77’. Interacts with ZBTB7B; the interaction allows the recruitment of HDAC4 on CD8 loci for deacetylation and possible inhibition of CD8 genes expression. Interacts with DHX36. Interacts with SIK3; this interaction leads to HDAC4 retention in the cytoplasm. Interacts with ZNF638.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Ubiquitous.

Post-translational modifications. Phosphorylated by CaMK4 at Ser-246, Ser-467 and Ser-632. Phosphorylation at other residues by CaMK2D is required for the interaction with 14-3-3. Phosphorylation at Ser-350, within the PxLPxI/L motif, impairs the binding of ANKRA2 but generates a high-affinity docking site for 14-3-3. Sumoylation on Lys-559 is promoted by the E3 SUMO-protein ligase RANBP2, and prevented by phosphorylation by CaMK4.

Disease relevance. HDAC4 point mutations and chromosomal microdeletions encompassing this gene have been found in patients with brachydactyly and intellectual disability syndrome. However, HDAC4 haploinsufficiency is not fully penetrant and multiple genes may contribute to manifestation of the full phenotypic spectrum. Neurodevelopmental disorder with central hypotonia and dysmorphic facies (NEDCHF) [MIM:619797] An autosomal dominant disease characterized by global developmental delay, impaired intellectual development, seizures, distinctive facial features, scoliosis, delayed closure of the anterior fontanel, and non-specific brain abnormalities. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The nuclear export sequence mediates the shuttling between the nucleus and the cytoplasm. The PxLPxI/L motif mediates interaction with ankyrin repeats of ANKRA2.

Similarity. Belongs to the histone deacetylase family. HD type 2 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P56524-1	1	yes
P56524-2	2

RefSeq proteins (8): NP_001365343, NP_001365344, NP_001365345, NP_001365346, NP_001422920, NP_001422921, NP_001422922, NP_006028 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000286	HDACs	Family
IPR023696	Ureohydrolase_dom_sf	Homologous_superfamily
IPR023801	His_deacetylse_dom	Domain
IPR024643	Hist_deacetylase_Gln_rich_N	Domain
IPR037138	His_deacetylse_dom_sf	Homologous_superfamily
IPR046949	HDAC4/5/7/9	Family

Pfam: PF00850, PF12203

Enzyme classification (BRENDA):

• EC 3.5.1.98 — histone deacetylase (BRENDA: 33 organisms, 161 substrates, 590 inhibitors, 88 Km, 32 kcat entries)

Substrate kinetics (BRENDA)

32 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
FLUOR DE LYS HDAC8 SUBSTRATE	0.14–1.1	9
AC-KHK(ACETYL)K(ACETYL)-7-AMIDO-4-METHYLCOUMARIN	0.273–2.403	6
FLUOR DE LYS HDAC SUBSTRATE	0.013–0.088	6
AC-FEK(ACETYL)-7-AMIDO-4-METHYLCOUMARIN	0.0023–0.0359	5
AC-GGK(ACETYL)-7-AMIDO-4-METHYLCOUMARIN	0.0043–0.0877	5
AC-GS(PO3)K(ACETYL)-7-AMIDO-4-METHYLCOUMARIN	0.0123–0.0666	5
AC-GSK(ACETYL)-7-AMIDO-4-METHYLCOUMARIN	0.004–0.0241	5
AC-IHK(ACETYL)-7-AMIDO-4-METHYLCOUMARIN	0.0007–0.108	5
AC-KYK(ACETYL)-7-AMIDO-4-METHYLCOUMARIN	0.0044–0.107	4
FLUOR DE LYS	—	4
AC-LYK(ACETYL)-7-AMIDO-4-METHYLCOUMARIN	0.0069–0.03	3
AC-VLK(ACETYL)-7-AMIDO-4-METHYLCOUMARIN	0.0119–0.0221	3
RHK(ACETYL)K(ACETYL)-FLUOROPHORE	0.16–1.1	3
AC-DQK(ACETYL)-7-AMIDO-4-METHYLCOUMARIN	0.0024–0.0165	2
BENZYLOXYCARBONYL-L-LYS(ACETYL)-7-AMIDO-4-METHYL	0.078–0.099	2

Catalyzed reactions (Rhea), 1 shown:

• N(6)-acetyl-L-lysyl-[histone] + H2O = L-lysyl-[histone] + acetate (RHEA:58196)

UniProt features (105 total): helix 25, mutagenesis site 21, strand 15, region of interest 9, modified residue 7, sequence variant 6, compositionally biased region 5, binding site 4, turn 4, short sequence motif 2, splice variant 2, chain 1, coiled-coil region 1, active site 1, cross-link 1, sequence conflict 1

Structure

Experimental structures (PDB)

19 structures.

PDB	Method	Resolution (Å)
3V31	X-RAY DIFFRACTION	1.57
2VQM	X-RAY DIFFRACTION	1.8
3UXG	X-RAY DIFFRACTION	1.85
5ZOO	X-RAY DIFFRACTION	1.85
3UZD	X-RAY DIFFRACTION	1.86
2VQQ	X-RAY DIFFRACTION	1.9
2VQJ	X-RAY DIFFRACTION	2.1
2VQO	X-RAY DIFFRACTION	2.15
6FYZ	X-RAY DIFFRACTION	2.15
8PDE	X-RAY DIFFRACTION	2.4
2H8N	X-RAY DIFFRACTION	2.6
5A2S	X-RAY DIFFRACTION	2.65
5ZOP	X-RAY DIFFRACTION	2.7
4CBY	X-RAY DIFFRACTION	2.72
2O94	X-RAY DIFFRACTION	3
2VQW	X-RAY DIFFRACTION	3
4CBT	X-RAY DIFFRACTION	3.03
2VQV	X-RAY DIFFRACTION	3.3
7XUZ	X-RAY DIFFRACTION	3.59

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P56524-F1	65.67	0.33

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): 803

Ligand- & substrate-binding residues (4): 667; 669; 675; 751

Post-translational modifications (8): 210, 246, 350, 467, 565, 632, 633, 559

Mutagenesis-validated functional residues (21):

Position	Phenotype
246	reduces phosphorylation and its subsequent nuclear export.
345	no effect on interaction with ankra2.
346	no effect on interaction with ankra2.
347	no effect on interaction with ankra2.
348	no effect on interaction with ankra2.
349	may affect interaction with ankra2.
349	decreased interaction with ankra2.
350	no effect on interaction with ankra2.
351	loss of interaction with ankra2.
352	loss of interaction with ankra2.
353	no effect on interaction with ankra2.
354	may affect interaction with ankra2.
354	loss of interaction with ankra2.
355	no effect on interaction with ankra2.
356	no effect on interaction with ankra2.
467	reduces phosphorylation and its subsequent nuclear export.
559	abolishes sumoylation and reduces the histone deacetylase activity.
632	reduces phosphorylation and its subsequent nuclear export.
803	abolishes histone deacetylase activity.
1056	reduces camk-dependent nuclear export.
1062	reduces camk-dependent nuclear export.

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-2122947	NOTCH1 Intracellular Domain Regulates Transcription
R-HSA-2644606	Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2894862	Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-350054	Notch-HLH transcription pathway
R-HSA-4090294	SUMOylation of intracellular receptors
R-HSA-4551638	SUMOylation of chromatin organization proteins
R-HSA-8941284	RUNX2 regulates chondrocyte maturation
R-HSA-8951936	RUNX3 regulates p14-ARF
R-HSA-9976102	Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)

MSigDB gene sets: 0 (showing top):

GO Biological Process (35): negative regulation of transcription by RNA polymerase II (GO:0000122), chromatin remodeling (GO:0006338), inflammatory response (GO:0006954), nervous system development (GO:0007399), positive regulation of cell population proliferation (GO:0008284), negative regulation of myotube differentiation (GO:0010832), obsolete negative regulation of transcription by competitive promoter binding (GO:0010944), response to denervation involved in regulation of muscle adaptation (GO:0014894), cardiac muscle hypertrophy in response to stress (GO:0014898), protein sumoylation (GO:0016925), B cell differentiation (GO:0030183), positive regulation of protein sumoylation (GO:0033235), epigenetic regulation of gene expression (GO:0040029), B cell activation (GO:0042113), negative regulation of gene expression, epigenetic (GO:0045814), negative regulation of glycolytic process (GO:0045820), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), type I interferon-mediated signaling pathway (GO:0060337), negative regulation of protein refolding (GO:0061084), response to interleukin-1 (GO:0070555), skeletal system development (GO:0001501), osteoblast differentiation (GO:0001649), osteoblast development (GO:0002076), chromatin organization (GO:0006325), protein deacetylation (GO:0006476), cell population proliferation (GO:0008283), negative regulation of cell population proliferation (GO:0008285), negative regulation of macromolecule biosynthetic process (GO:0010558), regulation of cardiac muscle contraction by calcium ion signaling (GO:0010882), negative regulation of osteoblast differentiation (GO:0045668), negative regulation of DNA-templated transcription (GO:0045892), regulation of skeletal muscle fiber development (GO:0048742), regulation of skeletal muscle fiber differentiation (GO:1902809), negative regulation of miRNA transcription (GO:1902894)

GO Molecular Function (22): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription activator activity (GO:0001216), histone deacetylase activity (GO:0004407), zinc ion binding (GO:0008270), SUMO transferase activity (GO:0019789), potassium ion binding (GO:0030955), protein lysine deacetylase activity (GO:0033558), identical protein binding (GO:0042802), histone deacetylase binding (GO:0042826), molecular adaptor activity (GO:0060090), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), DNA-binding transcription factor binding (GO:0140297), histone deacetylase activity, hydrolytic mechanism (GO:0141221), transcription cis-regulatory region binding (GO:0000976), DNA binding (GO:0003677), chromatin binding (GO:0003682), transcription corepressor activity (GO:0003714), protein binding (GO:0005515), hydrolase activity (GO:0016787), protein kinase binding (GO:0019901), histone binding (GO:0042393), metal ion binding (GO:0046872)

GO Cellular Component (10): histone deacetylase complex (GO:0000118), chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), nuclear speck (GO:0016607), transcription repressor complex (GO:0017053), neuromuscular junction (GO:0031594), actomyosin (GO:0042641)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
SUMO E3 ligases SUMOylate target proteins	2
Signaling by NOTCH1	1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1
Generic Transcription Pathway	1
RUNX2 regulates bone development	1
Transcriptional regulation by RUNX3	1
Differentiation of T cells	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
binding	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
negative regulation of DNA-templated transcription	2
positive regulation of DNA-templated transcription	2
chromatin organization	1
defense response	1
system development	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
regulation of myotube differentiation	1
myotube differentiation	1
negative regulation of striated muscle cell differentiation	1
response to muscle inactivity	1
regulation of muscle adaptation	1
muscle hypertrophy in response to stress	1
cardiac muscle hypertrophy	1
cardiac muscle adaptation	1
peptidyl-lysine modification	1
protein modification by small protein conjugation	1
lymphocyte differentiation	1
B cell activation	1
protein sumoylation	1
regulation of protein sumoylation	1
positive regulation of protein modification by small protein conjugation or removal	1
chromatin remodeling	1
regulation of gene expression	1
lymphocyte activation	1
negative regulation of gene expression	1
epigenetic regulation of gene expression	1
glycolytic process	1
regulation of glycolytic process	1
negative regulation of purine nucleotide catabolic process	1
negative regulation of carbohydrate metabolic process	1
negative regulation of ATP metabolic process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1

Protein interactions and networks

STRING

3914 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HDAC4	NCOR1	O75376	993
HDAC4	RUNX2	Q13950	979
HDAC4	HSP90AA1	P07900	971
HDAC4	HSP90AB1	P08238	957
HDAC4	NCOR2	Q9Y618	932
HDAC4	BCL6	P41182	925
HDAC4	SMAD3	P84022	920
HDAC4	ANKRA2	Q9H9E1	893
HDAC4	NUP155	O75694	889
HDAC4	MEF2C	Q06413	888
HDAC4	MEF2A	Q02078	863
HDAC4	YY1	P25490	856
HDAC4	ZBTB16	Q05516	843
HDAC4	MEF2D	Q14814	833
HDAC4	MYOD1	P15172	822

IntAct

228 interactions, top by confidence:

A	B	Type	Score
YWHAG	HDAC4	psi-mi:“MI:0915”(physical association)	0.950
HDAC4	YWHAG	psi-mi:“MI:0915”(physical association)	0.950
HDAC4	YWHAG	psi-mi:“MI:0914”(association)	0.950
HDAC4	YWHAZ	psi-mi:“MI:0915”(physical association)	0.900
YWHAZ	HDAC4	psi-mi:“MI:0915”(physical association)	0.900
HDAC4	YWHAE	psi-mi:“MI:0915”(physical association)	0.860
HDAC4	YWHAB	psi-mi:“MI:0914”(association)	0.830
YWHAH	ABLIM1	psi-mi:“MI:0914”(association)	0.800
SFN	HDAC4	psi-mi:“MI:0915”(physical association)	0.780
HDAC4	SFN	psi-mi:“MI:0915”(physical association)	0.780
YWHAH	FAM83G	psi-mi:“MI:0914”(association)	0.710
HDAC4	HDAC4	psi-mi:“MI:0407”(direct interaction)	0.650
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
HDAC4	EBNA-LP	psi-mi:“MI:0915”(physical association)	0.610
EBNA-LP	HDAC4	psi-mi:“MI:0914”(association)	0.610
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
MIF4GD	HDAC4	psi-mi:“MI:0915”(physical association)	0.600
HDAC4	MIF4GD	psi-mi:“MI:0915”(physical association)	0.600
HDAC4	MIF4GD	psi-mi:“MI:0403”(colocalization)	0.600
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570

BioGRID (629): HDAC4 (Biochemical Activity), HDAC4 (Two-hybrid), HDAC4 (Two-hybrid), HDAC4 (Two-hybrid), HDAC4 (Two-hybrid), HDAC4 (Two-hybrid), HDAC4 (Two-hybrid), MTUS2 (Two-hybrid), LDOC1 (Two-hybrid), EFEMP2 (Two-hybrid), ANKRA2 (Two-hybrid), RINT1 (Two-hybrid), CCDC136 (Two-hybrid), KRT40 (Two-hybrid), HDAC4 (Affinity Capture-Western)

ESM2 similar proteins: A0A571BF63, A0A8M9QN10, A2ARM1, A2CI97, A3KNA7, A4D1P6, A9C3W3, B2RYI0, E9Q7E2, F1QNV4, O95475, P49848, P56524, P70302, P83093, P84903, Q0VDN7, Q12769, Q12772, Q13586, Q2HJE1, Q32N92, Q3T1I5, Q3U1N2, Q3UGY8, Q58CP9, Q58HI1, Q5E9R0, Q5R902, Q5ZLL7, Q60429, Q62311, Q63801, Q6GQ26, Q6NZM9, Q6P4L9, Q6P4R8, Q6PIJ4, Q6ZPR5, Q7TMQ7

Diamond homologs: A0A8I6GM68, D2HBJ8, F1QCV2, O17323, O27262, O30107, P28606, P38748, P53973, P56523, P56524, P72702, P83038, Q09440, Q0V9G5, Q20296, Q2QWU2, Q3JUN4, Q54QE6, Q569C4, Q57955, Q5A960, Q5R902, Q5XGZ2, Q613L4, Q6NTR6, Q6NZM9, Q6P3E7, Q6P9L4, Q70CQ1, Q70I53, Q7Z569, Q7ZUM8, Q80ZH1, Q8C2B3, Q8C2S0, Q8GXJ1, Q8LRK8, Q8RX28, Q8WUI4

SIGNOR signaling

40 interactions.

A	Effect	B	Mechanism
RELA	up-regulates	HDAC4	binding
HDAC4	down-regulates	RUNX2	deacetylation
CAMK2D	up-regulates	HDAC4	phosphorylation
PPP2CA	up-regulates	HDAC4	dephosphorylation
GSK3B	down-regulates	HDAC4	phosphorylation
PRKAA1	down-regulates	HDAC4	phosphorylation
AURKB	down-regulates	HDAC4	phosphorylation
AMPK	down-regulates	HDAC4	phosphorylation
HDAC4	“down-regulates activity”	RUNX2	deacetylation
HDAC4	“down-regulates quantity by repression”	HOXB13	“transcriptional regulation”
HDAC4	“down-regulates quantity by repression”	MMP13	“transcriptional regulation”
BCORL1	“up-regulates activity”	HDAC4	binding
HDAC4	“down-regulates quantity by repression”	CDH1	“transcriptional regulation”
GATA1	“up-regulates activity”	HDAC4	relocalization
SIK3	“down-regulates activity”	HDAC4	phosphorylation
HDAC4	down-regulates	MEF2A	binding
HDAC4	down-regulates	MEF2C	binding
HDAC4	down-regulates	MEF2D	binding
CAMK4	down-regulates	HDAC4	phosphorylation
HDAC4	“down-regulates activity”	RUNX2	binding
CAMK4	“down-regulates activity”	HDAC4	phosphorylation
belinostat	“down-regulates activity”	HDAC4	“chemical inhibition”
panobinostat	“down-regulates activity”	HDAC4	“chemical inhibition”
“N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester”	“down-regulates activity”	HDAC4	“chemical inhibition”
vorinostat	“down-regulates activity”	HDAC4	“chemical inhibition”
N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide	“down-regulates activity”	HDAC4	“chemical inhibition”
“trichostatin A”	“down-regulates activity”	HDAC4	“chemical inhibition”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 122 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
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	8	76.8×	9e-12
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	8	76.8×	9e-12
Activation of BAD and translocation to mitochondria	7	76.1×	1e-10
Activation of BH3-only proteins	7	49.6×	3e-09
RHO GTPases activate PKNs	9	40.8×	8e-11
FOXO-mediated transcription	7	33.6×	6e-08
Intrinsic Pathway for Apoptosis	7	29.3×	1e-07
SARS-CoV-1-host interactions	8	20.1×	2e-07

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	6	20.9×	3e-04
substantia nigra development	5	17.4×	2e-03
intracellular protein localization	9	9.0×	3e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — THYM.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	8
Uncertain significance	298
Likely benign	217
Benign	130

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
1344563	NM_001378414.1(HDAC4):c.742C>G (p.Pro248Ala)	Pathogenic
1344564	NM_001378414.1(HDAC4):c.740A>G (p.Glu247Gly)	Pathogenic
151409	GRCh38/hg38 2q37.3(chr2:239045268-239678582)x1	Pathogenic
3340826	NM_001378414.1(HDAC4):c.339+1G>A	Pathogenic
424498	NM_001378414.1(HDAC4):c.743C>T (p.Pro248Leu)	Pathogenic
4685502	NM_001378414.1(HDAC4):c.739G>A (p.Glu247Lys)	Pathogenic
5069	NM_001378414.1(HDAC4):c.2414dup (p.Gly806fs)	Pathogenic
1199489	NM_001378414.1(HDAC4):c.1835_1840delinsTCCACCAGCTG (p.Asn612fs)	Likely pathogenic
1305765	NM_001378414.1(HDAC4):c.721C>T (p.Leu241Phe)	Likely pathogenic
1306095	NM_001378414.1(HDAC4):c.329del (p.Glu110fs)	Likely pathogenic
148279	GRCh38/hg38 2q37.3(chr2:239083430-239094006)x1	Likely pathogenic
441739	GRCh37/hg19 2q37.3(chr2:240203374-240432589)x1	Likely pathogenic
450529	NM_001378414.1(HDAC4):c.2628C>G (p.Phe876Leu)	Likely pathogenic
800319	NM_001378414.1(HDAC4):c.1580C>T (p.Pro527Leu)	Likely pathogenic
814377	GRCh37/hg19 2q37.3(chr2:239896860-240221984)x1	Likely pathogenic

SpliceAI

9662 predictions. Top by Δscore:

Variant	Effect	Δscore
2:239053454:GCTCA:G	donor_loss	1.0000
2:239053455:CTCA:C	donor_loss	1.0000
2:239053456:TCA:T	donor_loss	1.0000
2:239053457:CACCT:C	donor_loss	1.0000
2:239053458:A:AC	donor_gain	1.0000
2:239053459:C:CC	donor_gain	1.0000
2:239053459:CCT:C	donor_gain	1.0000
2:239053597:CTTGC:C	acceptor_gain	1.0000
2:239053601:CCT:C	acceptor_loss	1.0000
2:239053602:CT:C	acceptor_loss	1.0000
2:239053603:T:C	acceptor_loss	1.0000
2:239053607:G:GC	acceptor_gain	1.0000
2:239054747:A:AC	donor_gain	1.0000
2:239054748:C:CC	donor_gain	1.0000
2:239054829:TCAAG:T	acceptor_gain	1.0000
2:239054830:CAAG:C	acceptor_gain	1.0000
2:239054830:CAAGC:C	acceptor_gain	1.0000
2:239066716:TCCTA:T	donor_loss	1.0000
2:239066717:CCTA:C	donor_loss	1.0000
2:239066718:CTA:C	donor_loss	1.0000
2:239066719:TACC:T	donor_loss	1.0000
2:239066721:C:T	donor_loss	1.0000
2:239066753:T:TA	donor_gain	1.0000
2:239068482:CACTT:C	donor_loss	1.0000
2:239068483:ACTTA:A	donor_loss	1.0000
2:239068484:CTTA:C	donor_loss	1.0000
2:239068485:TTA:T	donor_loss	1.0000
2:239068486:T:TG	donor_loss	1.0000
2:239068487:A:AC	donor_gain	1.0000
2:239068488:C:CT	donor_gain	1.0000

AlphaMissense

7087 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:239082126:G:C	F871L	1.000
2:239082126:G:T	F871L	1.000
2:239082127:A:C	F871C	1.000
2:239082128:A:G	F871L	1.000
2:239082129:G:C	F870L	1.000
2:239082129:G:T	F870L	1.000
2:239082131:A:G	F870L	1.000
2:239082215:G:C	H842D	1.000
2:239082220:T:A	D840V	1.000
2:239082220:T:G	D840A	1.000
2:239084233:G:C	C813W	1.000
2:239084234:C:T	C813Y	1.000
2:239084236:A:C	F812L	1.000
2:239084236:A:T	F812L	1.000
2:239084238:A:G	F812L	1.000
2:239087581:G:C	H803D	1.000
2:239090098:A:G	W762R	1.000
2:239090098:A:T	W762R	1.000
2:239108146:G:C	C667W	1.000
2:239108148:A:G	C667R	1.000
2:239156659:C:A	R242S	1.000
2:239156659:C:G	R242S	1.000
2:239156660:C:A	R242M	1.000
2:239156660:C:G	R242T	1.000
2:239156663:A:T	L241H	1.000
2:239163875:A:G	L180P	1.000
2:239163878:A:T	V179D	1.000
2:239163880:A:C	F178L	1.000
2:239163880:A:T	F178L	1.000
2:239163881:A:C	F178C	1.000

dbSNP variants (sampled 300 via entrez): RS1000014485 (2:239187711 C>A), RS1000015351 (2:239260128 A>C), RS1000020194 (2:239249534 C>T), RS1000024797 (2:239213188 T>C), RS1000031519 (2:239124329 C>A,T), RS1000046550 (2:239207451 T>C), RS1000058105 (2:239180124 T>C), RS1000070656 (2:239285380 C>G,T), RS1000080605 (2:239371697 G>A), RS1000087500 (2:239095278 C>G), RS1000092944 (2:239214393 A>G), RS1000093509 (2:239299191 T>C), RS1000094640 (2:239385114 C>T), RS1000107087 (2:239144079 G>A,T), RS1000107888 (2:239114331 T>C)

Disease associations

OMIM: gene MIM:605314 | disease phenotypes: MIM:619797, MIM:600430, MIM:192350, MIM:254500

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with central hypotonia and dysmorphic facies	Strong	Autosomal dominant
2q37 microdeletion syndrome	Limited	Unknown

Mondo (7): neurodevelopmental disorder with central hypotonia and dysmorphic facies (MONDO:0859232), 2q37 microdeletion syndrome (MONDO:0010886), syndromic intellectual disability (MONDO:0000508), intellectual disability (MONDO:0001071), VACTERL/vater association (MONDO:0008642), plasma cell myeloma (MONDO:0009693), microcephaly (MONDO:0001149)

Orphanet (6): 2q37 microdeletion syndrome (Orphanet:1001), Rare genetic syndromic intellectual disability (Orphanet:183763), VACTERL/VATER association (Orphanet:887), Multiple myeloma (Orphanet:29073), AL amyloidosis (Orphanet:85443), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

113 total (30 of 113 shown, HPO-id order):

HPO	Term
HP:0000003	Multicystic kidney dysplasia
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000126	Hydronephrosis
HP:0000179	Thick lower lip vermilion
HP:0000233	Thin vermilion border
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000272	Malar flattening
HP:0000280	Coarse facial features
HP:0000283	Broad face
HP:0000311	Round face
HP:0000316	Hypertelorism
HP:0000400	Macrotia
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000430	Underdeveloped nasal alae
HP:0000445	Wide nose
HP:0000455	Broad nasal tip
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000483	Astigmatism
HP:0000490	Deeply set eye
HP:0000581	Blepharophimosis
HP:0000582	Upslanted palpebral fissure
HP:0000637	Long palpebral fissure
HP:0000646	Amblyopia
HP:0000684	Delayed eruption of teeth
HP:0000687	Widely spaced teeth

GWAS associations

24 associations (top):

Study	Trait	p-value
GCST001248_10	Pulmonary function	2.000000e-12
GCST001251_4	Pulmonary function	1.000000e-07
GCST001548_1	Male-pattern baldness	1.000000e-12
GCST001784_45	Pulmonary function (smoking interaction)	2.000000e-07
GCST001877_23	Autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia (combined)	8.000000e-06
GCST002892_10	Perioperative myocardial infarction in coronary artery bypass surgery	8.000000e-06
GCST004250_3	Alanine aminotransferase (ALT) levels after remission induction therapy in actute lymphoblastic leukemia (ALL)	7.000000e-06
GCST004792_4	Amyotrophic lateral sclerosis in C9orf72 mutation positive individuals	7.000000e-06
GCST005051_10	Obstructive sleep apnea trait (apnea hypopnea index)	7.000000e-07
GCST006010_5	Mean arterial pressure	5.000000e-08
GCST006627_75	Diastolic blood pressure	4.000000e-09
GCST006979_97	Heel bone mineral density	6.000000e-10
GCST006988_87	Blond vs. brown/black hair color	2.000000e-11
GCST007243_1	Intra-individual response time variability (selective attention)	3.000000e-08
GCST007243_2	Intra-individual response time variability (selective attention)	3.000000e-08
GCST007504_6	Nevus count	8.000000e-07
GCST007505_23	Nevus count or cutaneous melanoma	1.000000e-09
GCST007576_107	Chronotype	1.000000e-12
GCST007649_6	Estimated glomerular filtration rate after 5 years in renal transplantation (recipient effect)	8.000000e-06
GCST007703_81	Systolic blood pressure	2.000000e-06
GCST007704_50	Diastolic blood pressure	7.000000e-07
GCST007706_107	Mean arterial pressure	2.000000e-07
GCST010578_1	CV-A6-associated hand, foot, and mouth disease (severe vs mild)	5.000000e-06
GCST010989_210	Body size at age 10	3.000000e-08

EFO canonical traits (16, from GWAS)

EFO ID	Trait name
EFO:0003892	pulmonary function measurement
EFO:0004713	FEV/FVC ratio
EFO:0004314	forced expiratory volume
EFO:0007965	response to combination chemotherapy
EFO:0007817	sleep apnea measurement
EFO:0006340	mean arterial pressure
EFO:0006336	diastolic blood pressure
EFO:0009270	heel bone mineral density
EFO:0003924	hair color
EFO:0009702	intra-individual reaction time variability measurement
EFO:0004632	nevus count
EFO:0008328	chronotype measurement
EFO:0005199	renal transplant outcome measurement
EFO:0006335	systolic blood pressure
EFO:0007863	illness severity status
EFO:0009819	comparative body size at age 10, self-reported

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D009101	Multiple Myeloma	C04.557.595.500; C14.907.454.460; C15.378.147.780.650; C15.378.463.515.460; C20.683.515.845; C20.683.780.650
C538317	Chromosome 2q37 deletion syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (6): CHEMBL2093865 (PROTEIN FAMILY), CHEMBL3524 (SINGLE PROTEIN), CHEMBL4296127 (PROTEIN-PROTEIN INTERACTION), CHEMBL4630746 (PROTEIN-PROTEIN INTERACTION), CHEMBL6066585 (PROTEIN COMPLEX), CHEMBL6195587 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

31 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 464,065 (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
CHEMBL118	CELECOXIB	4	112,844
CHEMBL1469	PHENYLBUTANOIC ACID	4	37,081
CHEMBL1746	SODIUM PHENYLBUTYRATE	4	5,577
CHEMBL343448	ROMIDEPSIN	4	12,963
CHEMBL408513	BELINOSTAT	4	7,765
CHEMBL483254	PANOBINOSTAT	4	11,666
CHEMBL98	VORINOSTAT	4	50,361
CHEMBL1213492	GIVINOSTAT	4	2,827
CHEMBL487253	BENDAMUSTINE	4	30,877
CHEMBL140	CURCUMIN	3	93,882
CHEMBL145	CAFFEIC ACID	3	36,305
CHEMBL1851943	PRACINOSTAT	3	1,998
CHEMBL235191	TACEDINALINE	3	2,950
CHEMBL27759	ENTINOSTAT	3	6,584
CHEMBL3621988	TUCIDINOSTAT	3	2,182
CHEMBL2103863	ABEXINOSTAT	3	2,195
CHEMBL2107784	TASQUINIMOD	3	1,248
CHEMBL1801250	NANATINOSTAT	2	754
CHEMBL191482	AR-42	2	2,061
CHEMBL284616	CHLOROGENIC ACID	2	41,945
CHEMBL356066	DACINOSTAT	2
CHEMBL3622533	FIMEPINOSTAT	2
CHEMBL2105763	QUISINOSTAT	2
CHEMBL2364628	RICOLINOSTAT	2
CHEMBL3989941	TINOSTAMUSTINE	2
CHEMBL353581	PYROXAMIDE	1
CHEMBL598797	CUDC-101	1
CHEMBL609583	R-306465	1
CHEMBL96	GAMMA-AMINOBUTYRIC ACID	1
CHEMBL99	TRICHOSTATIN	1

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — 3.5.1.- Histone deacetylases (HDACs)

Most potent curated ligand interactions (14 total), top 14:

Ligand	Action	Affinity	Parameter
quisinostat	Inhibition	9.19	pIC50
tasquinimod	Inhibition	8.0	pKd
panobinostat	Inhibition	7.92	pEC50
CUDC-101	Inhibition	7.88	pIC50
romidepsin	Inhibition	7.69	pKi
TMP269	Inhibition	6.8	pIC50
belinostat	Inhibition	6.42	pKi
santacruzamate A	Inhibition	6.0	pIC50
givinostat	Inhibition	5.98	pKi
trichostatin A	Inhibition	5.85	pKi
martinostat	Inhibition	5.71	pIC50
dacinostat	Inhibition	5.65	pKi
KA1010	Inhibition	5.51	pIC50
scriptaid	Inhibition	5.12	pKi

Binding affinities (BindingDB)

480 measured of 664 human assays (666 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
MO-OH-PHE	KI	0.08 nM	US-9790158: Substituted tropolone derivatives and methods of use
Quinolone-based HDAC inhibitor 4i	IC50	0.1 nM
(E)-N-hydroxy-3-[4-[[2-(1-methylindol-3-yl)ethylamino]methyl]phenyl]prop-2-enamide	IC50	0.2 nM	US-10188756: Imaging histone deacetylases with a radiotracer using positron emission tomography
(E)-3-[4-[[1-adamantylmethyl(methyl)amino]methyl]phenyl]-N-hydroxyprop-2-enamide	IC50	0.3 nM	US-10188756: Imaging histone deacetylases with a radiotracer using positron emission tomography
MO-OH-NAP	KI	0.54 nM	US-9790158: Substituted tropolone derivatives and methods of use
(E)-3-[4-[(1-adamantylmethylamino)methyl]-3-fluorophenyl]-N-hydroxyprop-2-enamide	IC50	0.78 nM	US-10188756: Imaging histone deacetylases with a radiotracer using positron emission tomography
(E)-3-[4-[[1-adamantylmethyl(methyl)amino]methyl]-3-fluorophenyl]-N-hydroxyprop-2-enamide	IC50	0.78 nM	US-10188756: Imaging histone deacetylases with a radiotracer using positron emission tomography
N-hydroxy-6-(8-methoxy-6,11,11-trioxobenzo[b][1,4]benzothiazepin-5-yl)hexanamide	IC50	0.8 nM	US-10188756: Imaging histone deacetylases with a radiotracer using positron emission tomography
Panobinostat	IC50	1 nM
N-hydroxy-6-(8-methoxy-6-oxobenzo[b][1,4]benzothiazepin-5-yl)hexanamide	IC50	1.2 nM	US-10188756: Imaging histone deacetylases with a radiotracer using positron emission tomography
Quinolone-based HDAC inhibitor 4j	IC50	1.5 nM
2-hydroxy-6-(3-methoxyphenyl)cyclohepta-2,4,6-trien-1-one	KI	1.7 nM	US-9790158: Substituted tropolone derivatives and methods of use
(E)-3-[4-[(cyclohexylmethylamino)methyl]phenyl]-N-hydroxyprop-2-enamide	IC50	1.8 nM	US-10188756: Imaging histone deacetylases with a radiotracer using positron emission tomography
BRD2492	IC50	2 nM
NVP-LAQ824	IC50	2.6 nM
MO-OH-SM	KI	2.74 nM	US-9790158: Substituted tropolone derivatives and methods of use
3-anilino-1-[3-(cyanomethyl)-1-[(5-fluoro-2-methylphenyl)carbamoyl]azetidin-3-yl]pyrazole-4-carboxamide	IC50	3 nM	US-10047073
(R)-N-(1-(5-Azaspiro[2.5]octan-5- yl)propan-2-yl)-4-(5-(trifluoromethyl)- 1,2,4-oxadiazol-3-yl)benzamide	IC50	3 nM	US-10053434: Histone deacetylase inhibitors and compositions and methods of use thereof
2-hydroxy-6-isopropyl-cyclohepta-2,4,6-trien-1-one	KI	3.32 nM	US-9790158: Substituted tropolone derivatives and methods of use
N-((2R)-1-(3-Azabicyclo[3.2.0]heptan- 3-yl)propan-2-yl)-4-(5- (trifluoromethyl)-1,2,4-oxadiazol-3- yl)benzamide	IC50	4 nM	US-10053434: Histone deacetylase inhibitors and compositions and methods of use thereof
(E)-3-[2-butyl-1-[2-(dimethylamino)ethyl]benzimidazol-5-yl]-N-hydroxyprop-2-enamide	IC50	4.7 nM	US-10188756: Imaging histone deacetylases with a radiotracer using positron emission tomography
Z-L-Am7(betaMe)-QA (3)	IC50	4.9 nM
CHEBI:46024	IC50	4.9 nM
(E)-N-hydroxy-3-[3-[methyl(2-phenylethyl)sulfamoyl]phenyl]prop-2-enamide	IC50	5 nM	US-10188756: Imaging histone deacetylases with a radiotracer using positron emission tomography
R-TSA	IC50	5.76 nM
(R)-N-(1-(3,4-dihydro-2,7-naphthyridin- 2(1H)-yl)propan-2-yl)-4-(5- (trifluoromethyl)-1,2,4-oxadiazol-3- yl)benzamide	IC50	6 nM	US-10053434: Histone deacetylase inhibitors and compositions and methods of use thereof
2-N-hydroxy-5-N-[(1R)-1-phenylethyl]thiophene-2,5-dicarboxamide	IC50	6 nM
6-cyclopentyl-2-hydroxycyclohepta-2,4,6-trien-1-one	KI	6.64 nM	US-9790158: Substituted tropolone derivatives and methods of use
N-((R)-1-(3-Azabicyclo[3.2.1]octan-3- yl)propan-2-yl)-4-(5-(trifluoromethyl)- 1,2,4-oxadiazol-3-yl)benzamide	IC50	7 nM	US-10053434: Histone deacetylase inhibitors and compositions and methods of use thereof
HDAC inhibitor, Compound 2	IC50	7.93 nM
N-((2R)-1-(3-Azabicyclo[3.1.0]hexan-3- yl)propan-2-yl)-4-(5-(trifluoromethyl)- 1,2,4-oxadiazol-3-yl)benzamide	IC50	8 nM	US-10053434: Histone deacetylase inhibitors and compositions and methods of use thereof
(R)-N-(1-(5-Azaspiro[2.4]heptan-5- yl)propan-2-yl)-4-(5-(trifluoromethyl)- 1,2,4-oxadiazol-3-yl)benzamide	IC50	8 nM	US-10053434: Histone deacetylase inhibitors and compositions and methods of use thereof
(Z-L-Am7(S-)-QA)2 (4)	IC50	8.2 nM
(R)-N-(1-(3,4-Dihydroisoquinolin- 2(1H)-yl)propan-2-yl)-4-(5- (trifluoromethyl)-1,2,4-oxadiazol-3- yl)benzamide	IC50	9 nM	US-10053434: Histone deacetylase inhibitors and compositions and methods of use thereof
(2S)-1-((R)-2-(3-Fluoro-4-(5- (trifluoromethyl)-1,2,4-oxadiazol-3- yl)benzamido)propyl)-2- methylpyrrolidin-1-ium formate	IC50	9 nM	US-10053434: Histone deacetylase inhibitors and compositions and methods of use thereof
(1S)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoro-3-pyridinyl)-N-hydroxycyclopent-2-ene-1-carboxamide	IC50	10 nM	US-10106535: Histone deacetylase inhibitors and compositions and methods of use thereof
(1S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-quinoxalin-6-ylcyclopent-2-ene-1-carboxamide	IC50	10 nM	US-10106535: Histone deacetylase inhibitors and compositions and methods of use thereof
(1S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-imidazo[1,2-a]pyridin-7-ylcyclopent-2-ene-1-carboxamide	IC50	10 nM	US-10106535: Histone deacetylase inhibitors and compositions and methods of use thereof
(1S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(6-methyl-3-pyridinyl)cyclopent-2-ene-1-carboxamide	IC50	10 nM	US-10106535: Histone deacetylase inhibitors and compositions and methods of use thereof
(1S)-3-(5-chloro-6-methyl-3-pyridinyl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-ene-1-carboxamide	IC50	10 nM	US-10106535: Histone deacetylase inhibitors and compositions and methods of use thereof
(1S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(2-methyl-3-pyridinyl)cyclopent-2-ene-1-carboxamide	IC50	10 nM	US-10106535: Histone deacetylase inhibitors and compositions and methods of use thereof
(1S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-methylindazol-6-yl)cyclopent-2-ene-1-carboxamide	IC50	10 nM	US-10106535: Histone deacetylase inhibitors and compositions and methods of use thereof
(1S)-3-(1,3-benzothiazol-5-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-ene-1-carboxamide	IC50	10 nM	US-10106535: Histone deacetylase inhibitors and compositions and methods of use thereof
(1S)-1-(3,4-difluoro-2-methylphenyl)-N-hydroxy-3-(1-methylindazol-6-yl)cyclopent-2-ene-1-carboxamide	IC50	10 nM	US-10106535: Histone deacetylase inhibitors and compositions and methods of use thereof
(1S,2S,3S)-1-fluoro-2-[4-(5-fluoropyrimidin-2-yl)phenyl]-N-hydroxy-3-phenylcyclopropane-1-carboxamide	IC50	10 nM	US-9505736: Histone deacetylase inhibitors and compositions and methods of use thereof
(S)-benzyl 8-(hydroxyamino)-1,8-dioxo-1-(quinolin-8-ylamino)octan-2-ylcarbamate	IC50	10 nM
Quinolone-based HDAC inhibitor 4o	IC50	10 nM
HDAC inhibitor, Compound 1	IC50	10.1 nM
(R)-N-(1-(Azepan-1-yl)propan-2-yl)-4- (5-(trifluoromethyl)-1,2,4-oxadiazol-3- yl)benzamide	IC50	11 nM	US-10053434: Histone deacetylase inhibitors and compositions and methods of use thereof
2-((R)-2-(4-(5-(Trifluoromethyl)-1,2,4- oxadiazol-3- yl)benzamido)propyl)octahydrocyclopenta [c]pyrrol-2-ium formate	IC50	12 nM	US-10053434: Histone deacetylase inhibitors and compositions and methods of use thereof

ChEMBL bioactivities

4610 potent at pChembl≥5 of 5105 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.10	IC50	0.08	nM	CHEMBL3692689
10.10	Ki	0.08	nM	CHEMBL2408237
9.77	IC50	0.17	nM	CHEMBL5433552
9.70	IC50	0.2	nM	CHEMBL2371007
9.70	IC50	0.2	nM	CHEMBL5395502
9.70	IC50	0.2	nM	CHEMBL1793811
9.70	IC50	0.2	nM	CHEMBL1793991
9.70	IC50	0.2	nM	CHEMBL1793985
9.52	Ki	0.3	nM	QUISINOSTAT
9.52	IC50	0.3	nM	CHEMBL2370998
9.52	IC50	0.3	nM	CHEMBL5199116
9.52	IC50	0.3	nM	CHEMBL5170036
9.52	IC50	0.3	nM	CHEMBL1793822
9.52	IC50	0.3	nM	CHEMBL144205
9.46	IC50	0.35	nM	VORINOSTAT
9.40	IC50	0.4	nM	CHEMBL2371000
9.40	IC50	0.4	nM	CHEMBL1793816
9.27	Ki	0.54	nM	CHEMBL2408238
9.22	IC50	0.6	nM	QUISINOSTAT
9.22	Ki	0.6	nM	PANOBINOSTAT
9.19	IC50	0.64	nM	QUISINOSTAT
9.12	IC50	0.75	nM	CHEMBL3692678
9.08	IC50	0.83	nM	PANOBINOSTAT
9.07	IC50	0.85	nM	CHEMBL3692689
9.05	IC50	0.9	nM	CHEMBL605110
9.02	IC50	0.95	nM	CHEMBL595479
9.01	IC50	0.97	nM	CHEMBL3692671
9.00	IC50	1	nM	CHEMBL3758184
9.00	IC50	1	nM	APICIDIN
9.00	IC50	1	nM	CHEMBL2371003
9.00	IC50	1	nM	CHEMBL3692673
9.00	IC50	1	nM	ROMIDEPSIN
9.00	IC50	1	nM	CHEMBL4467135
9.00	IC50	1	nM	DACINOSTAT
9.00	IC50	1	nM	VORINOSTAT
9.00	IC50	1	nM	PANOBINOSTAT
9.00	IC50	1	nM	CHEMBL595711
9.00	IC50	1	nM	CHEMBL595910
9.00	IC50	1	nM	CHEMBL1793947
9.00	IC50	1	nM	CHEMBL1793810
9.00	IC50	1	nM	CHEMBL1793823
8.99	IC50	1.03	nM	CHEMBL1214760
8.98	IC50	1.05	nM	CHEMBL594544
8.96	IC50	1.1	nM	CHEMBL3692683
8.92	IC50	1.2	nM	CHEMBL3692676
8.92	IC50	1.2	nM	DACINOSTAT
8.92	IC50	1.2	nM	APICIDIN
8.92	IC50	1.2	nM	CHEMBL485514
8.92	IC50	1.2	nM	CHEMBL604796
8.92	IC50	1.2	nM	CHEMBL608416

PubChem BioAssay actives

2554 with measured affinity, of 6100 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
N-hydroxy-2-[4-(4-methylphenyl)sulfonylpiperazin-1-yl]-1,3-thiazole-5-carboxamide	1941741: Inhibition of HDAC (unknown origin)	ic50	0.0001	uM
1-[5-(hydroxyamino)-5-oxopentyl]-N-(4-methyl-1,3-thiazol-2-yl)-4-oxoquinoline-3-carboxamide	1794854: HDAC Activity screening from Article 10.3109/14756366.2013.827675: “Quinolone-based HDAC inhibitors.”	ic50	0.0001	uM
7-[4-[[4-[3-(tert-butylsulfamoyl)anilino]-5-methylpyrimidin-2-yl]amino]-2-fluorophenoxy]-N-hydroxyheptanamide	2031064: Inhibition of HDAC in human HeLa cells nuclear extract incubated for 30 mins by multiplate reader analysis	ic50	0.0002	uM
7-[4-[[4-[3-(tert-butylsulfamoyl)anilino]-5-methylpyrimidin-2-yl]amino]phenoxy]-N-hydroxyheptanamide	2031064: Inhibition of HDAC in human HeLa cells nuclear extract incubated for 30 mins by multiplate reader analysis	ic50	0.0002	uM
N-hydroxy-2-[4-[[(1-methylindol-3-yl)methylamino]methyl]piperidin-1-yl]pyrimidine-5-carboxamide	1236446: Inhibition of human HDAC4	ki	0.0003	uM
(9S,12R)-3-[(2S)-butan-2-yl]-9-(6-hydroxy-5-oxoheptyl)-6-[(1-methoxyindol-3-yl)methyl]-1,4,7,10-tetrazabicyclo[10.4.0]hexadecane-2,5,8,11-tetrone	1847765: Inhibition of HDAC (unknown origin)	ic50	0.0003	uM
(9S,12R)-3-[(2S)-butan-2-yl]-6-(1H-indol-3-ylmethyl)-9-(5-oxoheptyl)-1,4,7,10-tetrazabicyclo[10.4.0]hexadecane-2,5,8,11-tetrone	1847765: Inhibition of HDAC (unknown origin)	ic50	0.0003	uM
(3S,6S,9S,12R)-3-[(2S)-butan-2-yl]-9-(7-hydroxy-6-oxooctyl)-6-[(1-methoxyindol-3-yl)methyl]-1,4,7,10-tetrazabicyclo[10.4.0]hexadecane-2,5,8,11-tetrone	90356: Inhibitory concentration against human Histone deacetylase in Hela cells	ic50	0.0003	uM
(3S,6S,9S,12R)-3,6-dimethyl-9-[6-(oxiran-2-yl)-6-oxohexyl]-1,4,7,10-tetrazabicyclo[10.3.0]pentadecane-2,5,8,11-tetrone	90700: Inhibition of Histone deacetylase 4 in mammalian cells.	ic50	0.0003	uM
N-hydroxy-2-[4-[(E)-1-hydroxy-4-phenylbut-3-en-2-yl]piperazin-1-yl]pyrimidine-5-carboxamide	454842: Inhibition of HDAC in human HeLa cells extractt	ic50	0.0010	uM
2-[4-[(E)-4-(4-fluorophenyl)-1-hydroxybut-3-en-2-yl]piperazin-1-yl]-N-hydroxypyrimidine-5-carboxamide	454842: Inhibition of HDAC in human HeLa cells extractt	ic50	0.0010	uM
(3S,6R,9S,12R)-3-[(2S)-butan-2-yl]-6-[(1-methoxyindol-2-yl)methyl]-9-(6-oxooctyl)-1,4,10-triazabicyclo[10.4.0]hexadecane-2,5,8,11-tetrone	1622995: Inhibition of HDAC (unknown origin)	ic50	0.0010	uM
N-hydroxy-6-[(2S,5S,8S,11S)-8-(1H-indol-3-ylmethyl)-2-methyl-11-(2-methylpropyl)-3,6,9,13-tetraoxo-1,4,7,10-tetrazacyclotridec-5-yl]hexanamide	447991: Inhibition of HDAC in human HeLa cell nuclear extract after 30 mins by fluorimetric assay	ic50	0.0010	uM
N’-hydroxy-N-[(2R)-4-(methylamino)-3-oxo-1-phenylbutan-2-yl]octanediamide	90195: Concentration required to inhibit Histone Deacetylase (HDAC) from K562 erythroleukemia cells	ic50	0.0014	uM
(2E,4E,6R)-7-[4-(dimethylamino)phenyl]-N-hydroxy-4,6-dimethyl-7-oxohepta-2,4-dienamide	1273502: Inhibition of HDAC in human HeLa cell nuclear extract using BML-KI104 Fluor de Lys as substrate by fluorescence-based assay	ic50	0.0014	uM
N-hydroxy-2-[4-(naphthalen-2-ylmethyl)piperazin-1-yl]pyrimidine-5-carboxamide	454842: Inhibition of HDAC in human HeLa cells extractt	ic50	0.0015	uM
N-hydroxy-2-[4-[(E)-1-methoxy-4-phenylbut-3-en-2-yl]piperazin-1-yl]pyrimidine-5-carboxamide	454842: Inhibition of HDAC in human HeLa cells extractt	ic50	0.0015	uM
N-hydroxy-2-[4-[[[(E)-1-hydroxy-4-phenylbut-3-en-2-yl]amino]methyl]piperidin-1-yl]pyrimidine-5-carboxamide	454842: Inhibition of HDAC in human HeLa cells extractt	ic50	0.0015	uM
N-(1,3-benzothiazol-2-yl)-1-[5-(hydroxyamino)-5-oxopentyl]-4-oxoquinoline-3-carboxamide	1794854: HDAC Activity screening from Article 10.3109/14756366.2013.827675: “Quinolone-based HDAC inhibitors.”	ic50	0.0015	uM
(2S,4R)-1-[(2S)-3,3-dimethyl-2-[[2-[2-[2-[2-[2-[4-[propyl-[(2R)-2-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoyl]amino]propyl]amino]butoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetyl]amino]butanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1875228: Protac activity at VHL/HDAC4 in human Jurkat E6.1 cells assessed as induction of HDAC4 degradation preincubated with elacridar for 1 hr followed by compound addition and measured after 24 hrs by Western blot analysis	ec50	0.0016	uM
(3’S,9’S,12’R)-3’-methyl-9’-[5-(pyridin-2-yldisulfanyl)pentyl]spiro[1,3-dihydroindene-2,6’-1,4,7,10-tetrazabicyclo[10.3.0]pentadecane]-2’,5’,8’,11’-tetrone	309968: Inhibition of human HDAC4 expressed in 293T cells	ic50	0.0016	uM
(3S,9S,12R)-6,6-dimethyl-3-(phenylmethoxymethyl)-9-[5-(pyridin-2-yldisulfanyl)pentyl]-1,4,7,10-tetrazabicyclo[10.3.0]pentadecane-2,5,8,11-tetrone	309968: Inhibition of human HDAC4 expressed in 293T cells	ic50	0.0016	uM
N-hydroxy-2-[4-[(E)-4-phenylbut-3-en-2-yl]piperazin-1-yl]pyrimidine-5-carboxamide	454842: Inhibition of HDAC in human HeLa cells extractt	ic50	0.0017	uM
N-hydroxy-6-[4-(6-methoxynaphthalen-2-yl)triazol-1-yl]hexanamide	382342: Inhibition of human HDAC in HeLa cells by flour de lys assay	ic50	0.0018	uM
(3S,9S,12R)-3-benzyl-6,6-dimethyl-9-[5-(pyridin-2-yldisulfanyl)pentyl]-1,4,7,10-tetrazabicyclo[10.3.0]pentadecane-2,5,8,11-tetrone	309968: Inhibition of human HDAC4 expressed in 293T cells	ic50	0.0018	uM
2-[2-[2-[[(2E)-3-(3-bromo-4-hydroxyphenyl)-2-hydroxyiminopropanoyl]amino]ethyldisulfanyl]ethylamino]-2-oxoacetic acid	90530: Inhibitory concentration against isolated Histone deacetylase	ic50	0.0020	uM
(3S,6S,9S,12R)-3-[(2S)-butan-2-yl]-6-(1H-indol-3-ylmethyl)-9-(6-oxooctyl)-1,4,7,10-tetrazabicyclo[10.4.0]hexadecane-2,5,8,11-tetrone	81887: Inhibitory activity against histone deacetylase (HDAC) enzyme derived from partially purified extracts of human HeLa cells using [3H]11 as radioligand	ic50	0.0020	uM
6-[4-[[5-chloro-4-(4-chloroanilino)pyrimidin-2-yl]amino]pyrazol-1-yl]-N-hydroxyhexanamide	1550094: Inhibition of HDAC in human HeLa nuclear extract using Boc-Lys(acetyl)-AMC as substrate preincubated for 5 mins followed by substrate addition and measured after 30 mins by fluorescence assay	ic50	0.0020	uM
7-[4-[[5-chloro-4-(4-chloroanilino)pyrimidin-2-yl]amino]pyrazol-1-yl]-N-hydroxyheptanamide	1550094: Inhibition of HDAC in human HeLa nuclear extract using Boc-Lys(acetyl)-AMC as substrate preincubated for 5 mins followed by substrate addition and measured after 30 mins by fluorescence assay	ic50	0.0020	uM
4-[(E)-3-[[(2S)-1-(4-bromoanilino)-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-oxoprop-1-enyl]-N-hydroxybenzamide	1390020: Inhibition of HDAC in human HeLa cell nuclear extract using Boc-Lys (acetyl)-AMC as substrate preincubated for 5 mins followed by substrate addition measured after 30 mins by fluorescence assay	ic50	0.0020	uM
4-[(E)-3-[[(2S)-1-(4-fluoroanilino)-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-oxoprop-1-enyl]-N-hydroxybenzamide	1390020: Inhibition of HDAC in human HeLa cell nuclear extract using Boc-Lys (acetyl)-AMC as substrate preincubated for 5 mins followed by substrate addition measured after 30 mins by fluorescence assay	ic50	0.0020	uM
benzyl N-[7-(2-hydroxyethyldisulfanyl)-1-oxo-1-(quinolin-8-ylamino)heptan-2-yl]carbamate	1622973: Inhibition of HDAC4 (unknown origin)	ic50	0.0020	uM
N-[(2R)-1-(3,3-dimethylpiperidin-1-yl)propan-2-yl]-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide	1694577: Inhibition of HDAC4 (unknown origin) using Boc Lys(TFA) as substrate by fluorogenic assay	ic50	0.0020	uM
2-(6-ethoxy-3-pyridinyl)-N-[7-(hydroxyamino)-7-oxoheptyl]-9-(2-methoxy-3-pyridinyl)-8-oxo-7H-purine-6-carboxamide	2079009: Inhibition of HDAC in human HeLa cells nuclear extract	ic50	0.0020	uM
N-hydroxy-7-[5-(4-methoxyphenyl)-1,3-oxazol-2-yl]heptanamide	316872: Inhibition of HDAC from human K562 cells	ic50	0.0021	uM
N-hydroxy-6-[4-(4-methoxyphenyl)triazol-1-yl]hexanamide	382342: Inhibition of human HDAC in HeLa cells by flour de lys assay	ic50	0.0021	uM
tert-butyl (8R,9R,12S)-12-[[6-(hydroxyamino)-6-oxohexyl]carbamoyl]-9-(2-methylpropyl)-2-oxa-11-azabicyclo[12.2.2]octadeca-1(16),14,17-triene-8-carboxylate	90195: Concentration required to inhibit Histone Deacetylase (HDAC) from K562 erythroleukemia cells	ic50	0.0021	uM
6-[4-(4-bromoanilino)-7-methoxyquinazolin-6-yl]oxy-N-hydroxyhexanamide	1720096: Inhibition of HDAC (unknown origin)	ic50	0.0022	uM
7-[4-(4-bromoanilino)-7-methoxyquinazolin-6-yl]oxy-N-hydroxyheptanamide	1275247: Inhibition of HDAC in human HeLa cell nuclear extracts preincubated for 15 mins followed by addition of Fluor de Lys as substrate for 1 hr by fluorometric assay	ic50	0.0022	uM
(3S,6S,9S,12R)-6-benzyl-3,6-dimethyl-9-[5-(pyridin-2-yldisulfanyl)pentyl]-1,4,7,10-tetrazabicyclo[10.3.0]pentadecane-2,5,8,11-tetrone	309968: Inhibition of human HDAC4 expressed in 293T cells	ic50	0.0022	uM
(3S,3’S,9’S,12’R)-3’-methyl-9’-[5-(pyridin-2-yldisulfanyl)pentyl]spiro[1,2-dihydroindene-3,6’-1,4,7,10-tetrazabicyclo[10.3.0]pentadecane]-2’,5’,8’,11’-tetrone	309968: Inhibition of human HDAC4 expressed in 293T cells	ic50	0.0024	uM
N-hydroxy-7-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]heptanamide	316872: Inhibition of HDAC from human K562 cells	ic50	0.0025	uM
7-[5-(4-bromophenyl)-1,3-oxazol-2-yl]-N-hydroxyheptanamide	316872: Inhibition of HDAC from human K562 cells	ic50	0.0027	uM
6-[(3S,6S,9S,12R)-3,6-dimethyl-2,5,8,11-tetraoxo-1,4,7,10-tetrazabicyclo[10.3.0]pentadecan-9-yl]-N-hydroxyhexanamide	90700: Inhibition of Histone deacetylase 4 in mammalian cells.	ic50	0.0027	uM
(3S,9S,12R)-6,6-dimethyl-3-(3-phenylpropyl)-9-[5-(pyridin-2-yldisulfanyl)pentyl]-1,4,7,10-tetrazabicyclo[10.3.0]pentadecane-2,5,8,11-tetrone	309968: Inhibition of human HDAC4 expressed in 293T cells	ic50	0.0027	uM
(E)-N-hydroxy-3-[4-[2-(2-methyl-1H-indol-3-yl)ethylsulfamoyl]phenyl]prop-2-enamide	1187258: Inhibition of HDAC in human HeLa cells nuclear extracts incubated for 30 mins by fluorescent assay	ic50	0.0028	uM
6-[4-(2,4-dichloroanilino)-7-methoxyquinazolin-6-yl]oxy-N-hydroxyhexanamide	1256443: Inhibition of human HDAC in HeLa cell nuclear extract by fluorometric assay using Fluor de Lys substrate	ic50	0.0028	uM
7-[4-(2,4-dichloroanilino)-7-methoxyquinazolin-6-yl]oxy-N-hydroxyheptanamide	1915571: Inhibition of HDAC (unknown origin)	ic50	0.0028	uM
N-[(2S)-1-(hydroxyamino)-1-oxo-3-phenylpropan-2-yl]-2-propylpentanamide	2127941: Inhibition of HDAC4 (unknown origin) incubated for 30 mins by ELISA	ic50	0.0029	uM
N-[(2R)-1-[(3S)-3-(difluoromethoxy)piperidin-1-yl]propan-2-yl]-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide	1694577: Inhibition of HDAC4 (unknown origin) using Boc Lys(TFA) as substrate by fluorogenic assay	ic50	0.0030	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	8
trichostatin A	affects cotreatment, decreases expression	4
Valproic Acid	decreases expression, increases methylation, affects cotreatment	4
Estradiol	affects binding, increases expression	3
bisphenol A	affects cotreatment, affects methylation, decreases methylation, increases expression	2
Cisplatin	increases activity, decreases expression, decreases response to substance	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Aflatoxin B1	affects methylation, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
chlamydocin	decreases activity	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
manganese chloride	increases expression	1
benzo(e)pyrene	decreases methylation	1
periodate-oxidized adenosine	affects expression	1
N-acetyl-4-benzoquinoneimine	affects response to substance	1
aflatoxin B2	affects methylation	1
arsenic trichloride	decreases reaction, affects binding	1
monomethylarsonous acid	increases expression, affects cotreatment, decreases expression	1
PCB 180	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
MC1568	decreases reaction, increases expression	1
Bortezomib	decreases expression	1
Sunitinib	increases expression	1

ChEMBL screening assays

1941 unique, capped per target: 1919 binding, 13 admet, 6 functional, 3 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1003756	Binding	Inhibition of HDAC in human NB4 cells assessed as induction of histone H3 acetylation after 6 hrs by Western blot analysis	Design, synthesis and preliminary biological evaluation of new hydroxamate histone deacetylase inhibitors as potential antileukemic agents. — Bioorg Med Chem Lett
CHEMBL4346553	ADMET	Inhibition of HDAC in HUVEC using Boc-Lys(Ac)-AMC as substrate preincubated for 12 hrs followed by substrate addition and measured after 4 hrs by fluorimetry	Discovery of Novel Fungal Lanosterol 14α-Demethylase (CYP51)/Histone Deacetylase Dual Inhibitors to Treat Azole-Resistant Candidiasis. — J Med Chem
CHEMBL5049470	Functional	In vivo inhibition of HDAC in HEL cells xenografted in BALB/C mouse assessed as upregulation of caspase-9 levels at 5 to 10 mg/kg by immunohistochemical staining method	Evodiamine-Inspired Topoisomerase-Histone Deacetylase Dual Inhibitors: Novel Orally Active Antitumor Agents for Leukemia Therapy. — J Med Chem

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8H8	Abcam HCT 116 HDAC4 KO	Cancer cell line	Male
CVCL_B8WL	Abcam MCF-7 HDAC4 KO	Cancer cell line	Female
CVCL_B9JI	Abcam A-549 HDAC4 KO	Cancer cell line	Male
CVCL_GS97	GM23277	Transformed cell line	Female
CVCL_SR09	HAP1 HDAC4 (-) 1	Cancer cell line	Male
CVCL_SR10	HAP1 HDAC4 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT01238250	Not specified	RECRUITING	Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability