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): 813 total — 8 pathogenic, 10 likely-pathogenic (top 4% of genes corpus-wide)
• Regional missense constraint (gnomAD): 2 of 9 regions constrained (≈4% of expected missense variation)
• GTEx eGene: eQTL in 15 tissues, sQTL in 13 (q < 0.05)
• Phenotypes (HPO): 113
• ChEMBL bioactivity: 31 clinical-phase molecules tested; no curated mechanism-of-action drug
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types (inferred from mutation patterns)
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.19 (highly constrained)
• Transcription factor: yes — 24 downstream targets (CollecTRI)
• MANE Select transcript: NM_001378414
• Interaction hub: 3,468 STRING partners (top 2% of genes corpus-wide)

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: 41 — 28 protein_coding, 9 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

MANE Select: ENST00000543185

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 4, TSL 2: 1, TSL 3: 4, TSL 4: 3, TSL 5: 4

ENST00000543185, ENST00000345617, ENST00000430200, ENST00000445704, ENST00000446876, ENST00000454542, ENST00000460235, ENST00000461113, ENST00000463007, ENST00000487617, ENST00000493582, ENST00000494800, ENST00000495497, ENST00000496347, ENST00000535493, ENST00000553145, ENST00000685474, ENST00000690129, ENST00000896768, ENST00000896769, ENST00000896770, ENST00000896771, ENST00000913662, ENST00000913663, ENST00000913664, ENST00000913665, ENST00000913666, ENST00000913667, ENST00000913668, ENST00000913669, ENST00000913670, ENST00000913671, ENST00000913672, ENST00000913673, ENST00000971555, ENST00001115534, ENST00001115535, ENST00001115536, ENST00001115537, ENST00001115538, ENST00001143753

RefSeq mRNA: 11 — MANE Select: NM_001378414 NM_001378414, NM_001378415, NM_001378416, NM_001378417, NM_001435991, NM_001435992, NM_001435993, NM_001435994, NM_001435996, NM_001435998, 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.

Highest expression (Bgee): sural nerve, gluteal muscle, gastrocnemius, muscle of leg, tibialis anterior.

Genetic regulation across tissues (GTEx eQTL / sQTL)

HDAC4 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 15 tissues and its splicing (sQTL) in 13 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 28 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Esophagus Muscularis	sqtl	8.0e-62	-1.12	2:239180631:C:T
Muscle Skeletal	sqtl	5.0e-56	+1.50	2:239308870:C:T
Esophagus Muscularis	eqtl	3.7e-49	+0.53	2:239180017:G:A
Colon Sigmoid	sqtl	6.0e-45	-1.36	2:239185188:G:A
Esophagus Gastroesophageal Junction	sqtl	5.0e-27	-1.10	2:239185188:G:A
Whole Blood	sqtl	1.1e-21	-0.62	2:239187170:G:C
Esophagus Gastroesophageal Junction	eqtl	1.9e-20	+0.39	2:239185188:G:A
Colon Sigmoid	eqtl	3.3e-20	+0.42	2:239185188:G:A
Colon Transverse	sqtl	1.8e-14	-0.84	2:239185188:G:A
Artery Tibial	eqtl	1.1e-11	+0.24	2:239185188:G:A
Thyroid	eqtl	8.2e-09	-0.30	2:239384069:A:G
Skin Sun Exposed Lower leg	sqtl	2.8e-07	+0.39	2:239153849:C:T
Esophagus Mucosa	eqtl	1.0e-05	+0.20	2:239178920:G:A
Nerve Tibial	eqtl	2.9e-05	+0.24	2:239137733:T:C
Stomach	sqtl	5.9e-05	-0.67	2:239180631:C:T
Colon Transverse	eqtl	6.5e-04	+0.14	2:239180017:G:A
Prostate	sqtl	1.6e-03	+0.59	2:239159906:A:G
Bladder	eqtl	2.8e-03	+0.44	2:239185188:G:A
Heart Atrial Appendage	eqtl	4.9e-03	+0.16	2:239097116:G:C
Cells EBV-transformed lymphocytes	eqtl	6.2e-03	+1.37	2:239689879:G:A

FANTOM5 promoters

showing 10 of 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

showing 100 of 293 tissues 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
tibia	UBERON:0000979	83.62	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.36	gold quality
lower esophagus mucosa	UBERON:0035834	83.34	gold quality
testis	UBERON:0000473	83.19	gold quality
medial globus pallidus	UBERON:0002477	83.06	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	83.02	gold quality
esophagus	UBERON:0001043	82.83	gold quality
muscle tissue	UBERON:0002385	82.48	gold quality
occipital lobe	UBERON:0002021	82.18	gold quality
stromal cell of endometrium	CL:0002255	82.17	gold quality
bone marrow	UBERON:0002371	82.15	gold quality
colon	UBERON:0001155	82.14	gold quality
esophagus squamous epithelium	UBERON:0006920	82.14	gold quality
monocyte	CL:0000576	82.03	gold quality
parietal pleura	UBERON:0002400	81.82	gold quality
mononuclear cell	CL:0000842	81.78	gold quality
leukocyte	CL:0000738	81.75	gold quality
body of uterus	UBERON:0009853	81.75	gold quality
gingiva	UBERON:0001828	81.68	gold quality
endocervix	UBERON:0000458	81.65	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.62	gold quality
large intestine	UBERON:0000059	81.55	gold quality
skin of hip	UBERON:0001554	81.51	gold quality
tendon	UBERON:0000043	81.27	gold quality
granulocyte	CL:0000094	81.22	gold quality
ectocervix	UBERON:0012249	81.21	gold quality
gall bladder	UBERON:0002110	80.64	gold quality
globus pallidus	UBERON:0001875	80.60	gold quality
tendon of biceps brachii	UBERON:0008188	80.56	gold quality
ventricular zone	UBERON:0003053	80.48	gold quality
transverse colon	UBERON:0001157	80.35	gold quality
squamous epithelium	UBERON:0006914	80.24	gold quality
intestine	UBERON:0000160	80.15	gold quality
right adrenal gland	UBERON:0001233	80.07	gold quality
calcaneal tendon	UBERON:0003701	80.02	gold quality
pleura	UBERON:0000977	79.94	gold quality
adrenal tissue	UBERON:0018303	79.92	gold quality
mucosa of stomach	UBERON:0001199	79.91	gold quality
apex of heart	UBERON:0002098	79.87	gold quality
skin of leg	UBERON:0001511	79.78	gold quality
corpus callosum	UBERON:0002336	79.74	gold quality
right adrenal gland cortex	UBERON:0035827	79.73	gold quality
adrenal gland	UBERON:0002369	79.63	gold quality
tibial nerve	UBERON:0001323	79.53	gold quality
left adrenal gland	UBERON:0001234	79.50	gold quality
prefrontal cortex	UBERON:0000451	79.48	gold quality
left uterine tube	UBERON:0001303	79.44	gold quality
esophagus mucosa	UBERON:0002469	79.40	gold quality
zone of skin	UBERON:0000014	79.38	gold quality
fundus of stomach	UBERON:0001160	79.32	gold quality
vagina	UBERON:0000996	79.28	gold quality
skin of abdomen	UBERON:0001416	79.28	gold quality
epithelium of esophagus	UBERON:0001976	79.25	gold quality
left adrenal gland cortex	UBERON:0035825	79.19	gold quality
ovary	UBERON:0000992	79.10	gold quality
postcentral gyrus	UBERON:0002581	79.03	gold quality
adrenal cortex	UBERON:0001235	78.98	gold quality
myometrium	UBERON:0001296	78.97	gold quality
pituitary gland	UBERON:0000007	78.95	gold quality
right frontal lobe	UBERON:0002810	78.86	gold quality
anatomical system	UBERON:0000467	78.80	gold quality
multicellular organism	UBERON:0000468	78.71	gold quality
prostate gland	UBERON:0002367	78.70	gold quality
material anatomical entity	UBERON:0000465	78.68	gold quality
left ovary	UBERON:0002119	78.67	gold quality
frontal cortex	UBERON:0001870	78.58	gold quality
parietal lobe	UBERON:0001872	78.57	gold quality
neocortex	UBERON:0001950	78.53	gold quality
Brodmann (1909) area 9	UBERON:0013540	78.41	gold quality
superior frontal gyrus	UBERON:0002661	78.31	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

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Postcentral gyrus	tissue	40.5
Hippocampus	tissue	33.9	medium
Locus coeruleus	tissue	31.4
Choroid plexus	tissue	26.1
Tongue	tissue	24.9
Nucleus accumbens	tissue	24.5
Skeletal muscle	tissue	20.6	medium
Frontal cortex	tissue	18.9
Olfactory bulb	tissue	15.2
Hippocampal formation	tissue	13.9
Bone marrow	tissue	13.7	high
Cerebral cortex	tissue	13.2	medium
Somatosensory cortex	tissue	13.2
Insular cortex	tissue	12.0
Caudate putamen	tissue	11.8
Amygdala	tissue	11.6
Occipital cortex	tissue	11.6
Temporal cortex	tissue	11.5
Motor cortex	tissue	11.4
Prefrontal cortex	tissue	11.1
Entorhinal cortex	tissue	11.1
Retrosplenial cortex	tissue	10.8
Retrosplenial and cingulate cortex	tissue	10.6
Cerebellum	tissue	9.3	not detected
Hypothalamus	tissue	8.8
Superior colliculi	tissue	8.6
Spinal cord	tissue	8.3
Thalamus	tissue	8.0
Midbrain	tissue	7.9
Medulla oblongata	tissue	7.8
Pons	tissue	7.6
Substantia nigra	tissue	7.6
Septum	tissue	6.9
Corpus callosum	tissue	6.7
Periaqueductal gray	tissue	6.7
Ventral forebrain	tissue	6.5
Esophagus	tissue	6.3	high
Basal ganglia	tissue	5.8	low
Putamen	tissue	5.8
Thymus	tissue	5.5
Endometrium 1	tissue	5.2	medium
Gallbladder	tissue	5.0	medium
Fallopian tube	tissue	4.9	high
Cervix	tissue	4.8	high
Testis	tissue	4.8	medium
Ovary	tissue	4.5	medium
Seminal vesicle	tissue	4.0	high
Appendix	tissue	4.0	high
Smooth muscle	tissue	3.8	high
Adrenal gland	tissue	3.7	medium
Spleen	tissue	3.6	medium
Colon	tissue	3.5	high
Pancreas	tissue	3.5	medium
Heart muscle	tissue	3.4	medium
Small intestine	tissue	3.3	high
Adipose tissue	tissue	3.1	not detected
Prostate	tissue	3.1	not detected
Thyroid gland	tissue	2.8	medium
Urinary bladder	tissue	2.5	high
Salivary gland	tissue	2.4	high

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Temporo-occipital transitional zone (56.1), Claustrum (52.6), Ventral periolivary nuclei (51.3), Precentral gyrus (49.2), Nucleus raphe magnus (48.6).

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)

Targeting HDAC4 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 214 miRNAs:

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

gnomAD constraint: pLI 1, LOEUF 0.192, missense Z 3.76 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000543185 splits into 9 regions with different missense tolerance; 2 are missense-constrained (≈4% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
2:239,053,100–239,066,733	131 / 130.6	1.00	no
2:239,066,734–239,090,070	189 / 317.6	0.60	no
2:239,090,071–239,102,796	49 / 55.6	0.88	no
2:239,102,797–239,111,535	47 / 117.2	0.40	no
2:239,111,536–239,126,466	196 / 210.7	0.93	no
2:239,126,467–239,126,553	7 / 30.5	0.23	yes (p 2.1e-05)
2:239,126,554–239,144,658	272 / 309.7	0.88	no
2:239,144,659–239,156,671	5 / 29.8	0.17	yes (p 5.4e-06)
2:239,156,672–239,352,699	247 / 310.0	0.80	no
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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:3036234) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 38 distinct phenotype terms.

Mouse phenotype (MP)	Records
increased anxiety-related response	2
increased grooming behavior	2
abnormal operant conditioning behavior	2
abnormal trabecular bone morphology	1
abnormal vertebrae morphology	1
abnormal long bone hypertrophic chondrocyte zone	1
domed cranium	1
exencephaly	1
convulsive seizures	1
decreased body weight	1
decreased body size	1
decreased locomotor activity	1
abnormal eating behavior	1
abnormal food preference	1
increased thermal nociceptive threshold	1
increased blinking frequency	1
decreased vertical activity	1
tonic seizures	1
increased circulating alkaline phosphatase level	1
increased coping response	1
premature endochondral bone ossification	1
abnormal involuntary movement	1
decreased aggression towards mice	1
abnormal motor nerve collateral sprouting	1
decreased length of long bones	1

+13 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Staphylococcus aureus subsp. aureus Mu50	P64375	100.0%	Diamond
Staphylococcus aureus subsp. aureus N315	P64376	100.0%	Diamond
Staphylococcus aureus subsp. aureus MSSA476	Q6G8J2	100.0%	Diamond
Staphylococcus aureus subsp. aureus MW2	Q8NW34	100.0%	Diamond
Staphylococcus aureus subsp. aureus COL	Q5HF39	99.7%	Diamond
Pongo abelii	Q5RB76	99.5%	Diamond
Staphylococcus aureus subsp. aureus MRSA252	Q6GFX3	98.5%	Diamond
Xenopus tropicalis	Q28DV3	98.4%	Diamond
Xenopus laevis	Q6IRL9	98.4%	Diamond
Gallus gallus	P56520	97.4%	Diamond
Cricetulus griseus	Q80ZH1	97.0%	Diamond
Tetraodon nigroviridis	Q4SFA0	96.7%	Diamond
Oryza sativa Japonica Group	Q6YV04	95.9%	Diamond
Arabidopsis thaliana	Q8H0W2	95.5%	Diamond
Caenorhabditis briggsae	Q613L4	82.2%	Diamond
Zea mays	P56521	81.5%	Diamond
Pseudomonas aeruginosa PAO1	Q9HXM1	75.0%	Diamond
Schizosaccharomyces pombe 972h-	O59702	66.6%	Diamond
Saccharomyces cerevisiae S288C	P32561	66.6%	Diamond
Mycoplana ramosa	Q48935	52.0%	Diamond
Candida albicans SC5314	Q5A960	50.4%	Diamond
Alcaligenaceae bacterium FB188	Q70I53	47.9%	Diamond
Burkholderia pseudomallei 1710b	Q3JUN4	43.5%	Diamond
Archaeoglobus fulgidus DSM 4304	O30107	40.8%	Diamond
Synechocystis sp. PCC 6803 substr. Kazusa	P72702	40.8%	Diamond
Methanothermobacter thermautotrophicus str. Delta H	O27262	39.7%	Diamond
Methanocaldococcus jannaschii DSM 2661	Q57955	38.1%	Diamond
Picosynechococcus sp. PCC 7002	P28606	37.7%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
MIR2467	ncRNA	100616360
HDAC4-AS1	ncRNA	101928111
HDAC4-AS2	ncRNA	138842259
MIR4269	ncRNA	100423043
MIR4441	ncRNA	100616493
TWIST2	protein-coding	117581
LINC01940	ncRNA	401039
MIR4440	ncRNA	100616397
LINC02991	ncRNA	401040

Protein

Protein identifiers

Histone deacetylase 4 — P56524 (reviewed: P56524)

All UniProt accessions (6): A0A7I2SVS4, C9J0X4, C9J481, P56524, 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 (11): NP_001365343, NP_001365344, NP_001365345, NP_001365346, NP_001422920, NP_001422921, NP_001422922, NP_001422923, NP_001422925, NP_001422927, 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)

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

UniProt features (112 total): helix 32, mutagenesis site 21, strand 15, region of interest 9, modified residue 7, sequence variant 6, compositionally biased region 5, turn 4, binding site 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 by resolution:

PDB	Title	Method	Resolution (Å)
3V31	Crystal Structure of the Peptide Bound Complex of the Ankyrin Repeat Domains of Human …	X-RAY DIFFRACTION	1.57
2VQM	Structure of HDAC4 catalytic domain bound to a hydroxamic acid inhbitor	X-RAY DIFFRACTION	1.8
3UXG	Crystal structure of RFXANK	X-RAY DIFFRACTION	1.85
5ZOO	Crystal structure of histone deacetylase 4 (HDAC4) in complex with a SMRT corepressor SP1 …	X-RAY DIFFRACTION	1.85
3UZD	Crystal structure of 14-3-3 GAMMA	X-RAY DIFFRACTION	1.86
2VQQ	Structure of HDAC4 catalytic domain (a double cysteine-to-alanine mutant) bound to a …	X-RAY DIFFRACTION	1.9
2VQJ	Structure of HDAC4 catalytic domain bound to a trifluoromethylketone inhbitor	X-RAY DIFFRACTION	2.1
2VQO	Structure of HDAC4 catalytic domain with a gain-of-function muation bound to a …	X-RAY DIFFRACTION	2.15
6FYZ	Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa …	X-RAY DIFFRACTION	2.15
8PDE	Crystal Structure of the MADS-box/MEF2 Domain of MEF2D bound to dsDNA and HDAC4 …	X-RAY DIFFRACTION	2.4
2H8N	Structure of a glutamine-rich domain from histone deacetylase 4	X-RAY DIFFRACTION	2.6
5A2S	Potent, selective and CNS-penetrant tetrasubstituted cyclopropane class IIa histone …	X-RAY DIFFRACTION	2.65
5ZOP	Crystal structure of histone deacetylase 4 (HDAC4) in complex with a SMRT corepressor SP2 …	X-RAY DIFFRACTION	2.7
4CBY	Design, synthesis, and biological evaluation of potent and selective Class IIa HDAC …	X-RAY DIFFRACTION	2.72
2O94	The 97H/F mutant Structure of a glutamine-rich domain from histone deacetylase 4	X-RAY DIFFRACTION	3
2VQW	Structure of inhibitor-free HDAC4 catalytic domain (with gain-of- function mutation …	X-RAY DIFFRACTION	3
4CBT	Design, synthesis, and biological evaluation of potent and selective Class IIa HDAC …	X-RAY DIFFRACTION	3.03
2VQV	Structure of HDAC4 catalytic domain with a gain-of-function mutation bound to a …	X-RAY DIFFRACTION	3.3
7XUZ	Crystal structure of a HDAC4-MEF2A-DNA ternary complex	X-RAY DIFFRACTION	3.59

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Predicted intracellular proteins, Disease related genes, FDA approved drug targets, Small molecule drugs, Human disease related genes, Congenital malformations, Congenital malformations of the nervous system, Other congenital disorders, Chromosomal abnormalities

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nuclear speckles; cytosol; nucleoplasm

Antibody reliability (HPA): IH approved · IF supported

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)

Position	Role
803

Ligand- & substrate-binding residues (4)

Position	Role
667	Zn(2+)
669	Zn(2+)
675	Zn(2+)
751	Zn(2+)

Post-translational modifications (8)

Type	Positions
Phosphoserine	210, 246, 350, 467, 565, 632, 633
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in sumo)	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

6 curated (TAS) of 27; 7 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

27 pathways:

ID	Pathway	Evidence
R-HSA-2894862	Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants ⚕	curated
R-HSA-2644606	Constitutive Signaling by NOTCH1 PEST Domain Mutants ⚕	curated
R-HSA-350054	Notch-HLH transcription pathway	curated
R-HSA-8951936	RUNX3 regulates p14-ARF	curated
R-HSA-4551638	SUMOylation of chromatin organization proteins	curated
R-HSA-4090294	SUMOylation of intracellular receptors	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers ⚕	—
R-HSA-2894858	Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer ⚕	—
R-HSA-2644602	Signaling by NOTCH1 PEST Domain Mutants in Cancer ⚕	—
R-HSA-2644603	Signaling by NOTCH1 in Cancer ⚕	—
R-HSA-9976102	Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	electronic
R-HSA-74160	Gene expression (Transcription)	—
R-HSA-212436	Generic Transcription Pathway	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-2122947	NOTCH1 Intracellular Domain Regulates Transcription	electronic
R-HSA-597592	Post-translational protein modification	—
R-HSA-73857	RNA Polymerase II Transcription	—
R-HSA-8941326	RUNX2 regulates bone development	—
R-HSA-8941284	RUNX2 regulates chondrocyte maturation	electronic
R-HSA-3108232	SUMO E3 ligases SUMOylate target proteins	—
R-HSA-2990846	SUMOylation	—
R-HSA-162582	Signal Transduction	—
R-HSA-157118	Signaling by NOTCH	—
R-HSA-1980143	Signaling by NOTCH1	—
R-HSA-8878166	Transcriptional regulation by RUNX2	—
R-HSA-8878159	Transcriptional regulation by RUNX3	—

MSigDB gene sets: 0 (showing top):

GO Biological Process (23): negative regulation of transcription by RNA polymerase II (GO:0000122), chromatin remodeling (GO:0006338), DNA-templated transcription (GO:0006351), inflammatory response (GO:0006954), nervous system development (GO:0007399), positive regulation of cell population proliferation (GO:0008284), negative regulation of myotube differentiation (GO:0010832), 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), chromatin organization (GO:0006325), 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

15 top-level categories:

Category	Pathways
SUMO E3 ligases SUMOylate target proteins	2
Signaling by NOTCH1 in Cancer	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
Signal Transduction	1
Signaling by NOTCH	1
RNA Polymerase II Transcription	1
Diseases of signal transduction by growth factor receptors and second messengers	1
Post-translational protein modification	1
SUMOylation	1

GO top-level categories

showing 60 of 84 GO namespaces:

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
gene expression	1
RNA biosynthetic process	1
defense response	1
system development	1
animal gross anatomical part developmental process	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
cellular response to type I interferon	1
interferon-mediated signaling pathway	1
protein refolding	1
regulation of protein refolding	1
negative regulation of protein folding	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
cis-regulatory region sequence-specific DNA binding	1
transcription cis-regulatory region binding	1
DNA-binding transcription factor activity	1
protein lysine deacetylase activity	1
histone modifying activity	1
transition metal ion binding	1
ubiquitin-like protein transferase activity	1
alkali metal ion binding	1
deacetylase activity	1
catalytic activity, acting on a protein	1
protein binding	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 30 of 56 annotations. The rest are phylogenetic / computational / electronic (IEA).

30 experimentally-supported GO terms:

GO term	NS	Evidence
chromatin remodeling	BP	direct assay
negative regulation of gene expression, epigenetic	BP	direct assay
negative regulation of myotube differentiation	BP	mutant phenotype
negative regulation of protein refolding	BP	direct assay
negative regulation of transcription by RNA polymerase II	BP	direct assay
positive regulation of cell population proliferation	BP	mutant phenotype
positive regulation of protein sumoylation	BP	direct assay
positive regulation of transcription by RNA polymerase II	BP	mutant phenotype
response to interleukin-1	BP	mutant phenotype
type I interferon-mediated signaling pathway	BP	direct assay
chromatin	CC	direct assay
cytoplasm	CC	direct assay
cytosol	CC	direct assay
histone deacetylase complex	CC	direct assay
nuclear speck	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
transcription repressor complex	CC	direct assay
DNA-binding transcription activator activity	MF	direct assay
DNA-binding transcription factor binding	MF	physical interaction
RNA polymerase II cis-regulatory region sequence-specific DNA binding	MF	direct assay
RNA polymerase II-specific DNA-binding transcription factor binding	MF	physical interaction
SUMO transferase activity	MF	experiment
histone deacetylase activity	MF	direct assay
histone deacetylase binding	MF	physical interaction
identical protein binding	MF	physical interaction
molecular adaptor activity	MF	direct assay
potassium ion binding	MF	direct assay
protein lysine deacetylase activity	MF	direct assay
zinc ion binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 3,468 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HDAC4	SIRT1	Q96EB6	764
HDAC4	SRF	P11831	726
HDAC4	RUNX2	Q13950	709
HDAC4	MEF2A	Q02078	704
HDAC4	MYOG	P15173	702
HDAC4	MEF2C	Q06413	699
HDAC4	MEF2D	Q14814	683
HDAC4	MYOD1	P15172	680
HDAC4	NCOR1	O75376	652
HDAC4	SIRT2	Q8IXJ6	648
HDAC4	NCOR2	Q9Y618	632
HDAC4	KAT2B	Q92831	617
HDAC4	CABIN1	Q9Y6J0	610
HDAC4	HDAC3	O15379	607
HDAC4	HDAC11	Q96DB2	598

IntAct

Human interaction partners of HDAC4 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 103 partners by confidence:

Partner	Interaction type	MIscore	Records
YWHAG	physical association	0.950	8
YWHAZ	physical association	0.900	4
YWHAH	association	0.890	1
YWHAE	physical association	0.860	5
YWHAB	association	0.830	1
YWHAQ	association	0.830	1
SFN	physical association	0.780	4
EBNA-LP	physical association	0.610	3
MIF4GD	physical association	0.600	4
ANKRA2	physical association	0.560	3
CCDC136	physical association	0.560	3
CDR2	physical association	0.560	3
EFEMP2	physical association	0.560	3
GOLGA2	physical association	0.560	3
KRT31	physical association	0.560	3
KRT38	physical association	0.560	3
KRT40	physical association	0.560	3
LDOC1	physical association	0.560	3
MTUS2	physical association	0.560	3
PNMA1	physical association	0.560	3
RINT1	physical association	0.560	3
RUNX3	physical association	0.560	1
AR	physical association	0.540	4
HDAC3	association	0.530	2
NCOR1	association	0.530	1
ICP0	physical association	0.520	3
BRMS1	physical association	0.520	2
UBE2I	physical association	0.510	3
BCL6	association	0.500	2
MEF2A	colocalization	0.490	2

BioGRID (630 interactions; top human partners by supporting records in a sample of 600 records): MEF2C (Affinity Capture-Western; 10 records), NCOR1 (Affinity Capture-MS; 10 records), YWHAQ (Affinity Capture-MS; 10 records), HDAC3 (Affinity Capture-MS; 9 records), YWHAB (Affinity Capture-MS; 8 records), YWHAE (Affinity Capture-MS; 8 records), YWHAG (Two-hybrid; 8 records), CAMK2D (Affinity Capture-MS; 7 records), AR (Reconstituted Complex; 6 records), HIF1A (Two-hybrid; 6 records), MEF2D (Biochemical Activity; 6 records), NCOR2 (Affinity Capture-MS; 6 records), YWHAH (Affinity Capture-MS; 6 records), YWHAZ (Affinity Capture-MS; 6 records), ANKRA2 (Two-hybrid; 5 records)

SIGNOR signaling

showing 31 of 40 signaling 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”
romidepsin	“down-regulates activity”	HDAC4	“chemical inhibition”
6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide	“down-regulates activity”	HDAC4	“chemical inhibition”
CUDC-101	“down-regulates activity”	HDAC4	“chemical inhibition”
PKA	“up-regulates activity”	HDAC4	phosphorylation

Protein complexes (CORUM) (10)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

10 complexes by size:

Complex	Subunits	Members
★ GNB1-GNG2-HDAC4 complex	3	HDAC4, GNB1, GNG2
★ BCL6-HDAC4 complex	2	BCL6, HDAC4
★ ACTN4-HDAC4 complex	2	ACTN4, HDAC4
★ HDAC4-ERK1 complex	2	HDAC4, MAPK3
★ HDAC4-ERK2 complex	2	HDAC4, MAPK1
★ HDAC4-NCOR2 complex	2	HDAC4, NCOR2
★ HDAC4-HDAC9 complex	2	HDAC4, HDAC9
★ HDAC4-MEF2A complex	2	HDAC4, MEF2A
★ HDAC4-MEF2C complex	2	HDAC4, MEF2C
★ HDAC4-MEF2D complex	2	HDAC4, MEF2D

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 103 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	84.0×	4e-12
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	8	84.0×	4e-12
Activation of BAD and translocation to mitochondria	7	83.3×	8e-11
Activation of BH3-only proteins	7	54.3×	2e-09
RHO GTPases activate PKNs	9	44.6×	3e-11
FOXO-mediated transcription	7	36.7×	3e-08
Intrinsic Pathway for Apoptosis	7	32.0×	7e-08
Expression of BMAL (ARNTL), CLOCK, and NPAS2	5	22.9×	4e-05

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	6	23.4×	1e-04
substantia nigra development	5	19.5×	1e-03
intracellular protein localization	9	10.0×	1e-04

Disease & clinical

Cancer significance

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

intOGen’s role is a computational inference from cohort mutation patterns and may diverge from the gene’s curated/literature role; read it alongside the evidence above.

Genetic variants

Variant evidence for HDAC4: 813 ClinVar records (18 pathogenic / likely pathogenic); 24 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	10
Uncertain significance	316
Likely benign	251
Benign	117

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 18 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
424498	NM_001378414.1(HDAC4):c.743C>T (p.Pro248Leu)	Pathogenic	criteria provided, multiple submitters, no conflicts	8
5069	NM_001378414.1(HDAC4):c.2414dup (p.Gly806fs)	Pathogenic	criteria provided, single submitter	2
3340826	NM_001378414.1(HDAC4):c.339+1G>A	Pathogenic	criteria provided, single submitter	1
4685502	NM_001378414.1(HDAC4):c.739G>A (p.Glu247Lys)	Pathogenic	criteria provided, single submitter	1
4976696	NM_001378414.1(HDAC4):c.1336C>T (p.Gln446Ter)	Pathogenic	criteria provided, single submitter	1
450529	NM_001378414.1(HDAC4):c.2628C>G (p.Phe876Leu)	Likely pathogenic	criteria provided, single submitter	1
450837	NM_001378414.1(HDAC4):c.2150del (p.Gln717fs)	Likely pathogenic	criteria provided, single submitter	1
1199489	NM_001378414.1(HDAC4):c.1835_1840delinsTCCACCAGCTG (p.Asn612fs)	Likely pathogenic	criteria provided, single submitter	1
1305765	NM_001378414.1(HDAC4):c.721C>T (p.Leu241Phe)	Likely pathogenic	criteria provided, single submitter	1
1306095	NM_001378414.1(HDAC4):c.329del (p.Glu110fs)	Likely pathogenic	criteria provided, single submitter	1
3390499	NM_001378414.1(HDAC4):c.3173C>A (p.Ala1058Asp)	Likely pathogenic	criteria provided, single submitter	1
1344563	NM_001378414.1(HDAC4):c.742C>G (p.Pro248Ala)	Pathogenic	no assertion criteria provided	1
1344564	NM_001378414.1(HDAC4):c.740A>G (p.Glu247Gly)	Pathogenic	no assertion criteria provided	1
800319	NM_001378414.1(HDAC4):c.1580C>T (p.Pro527Leu)	Likely pathogenic	no assertion criteria provided	1
151409	GRCh38/hg38 2q37.3(chr2:239045268-239678582)x1	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore HDAC4’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 40 predictions of 4,635):

Position(s)	Effect	Δscore	Sites
2:239053458–239053459	donor_loss	1.0000	5
2:239053602–239053603	acceptor_loss	1.0000	3
2:239066720–239066721	donor_loss	1.0000	5
2:239068487–239068488	donor_loss	1.0000	4
2:239068608–239068609	acceptor_loss	1.0000	6
2:239081193–239081194	acceptor_loss	1.0000	6
2:239081200–239081201	acceptor_gain	1.0000	2
2:239082100–239082101	donor_loss	1.0000	5
2:239082222–239082223	acceptor_loss	1.0000	3
2:239082223	acceptor_gain	1.0000

AlphaMissense

2,892 missense substitutions predicted likely pathogenic (of 7,087 scored), across 673 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M662	9	0.933	0.997
M810	9	0.899	0.993
H803	8	0.999	1.000
D840	8	0.998	1.000
H802	8	0.997	0.999
H842	8	0.997	1.000
D934	8	0.997	0.999
D757	8	0.996	0.999
H843	8	0.996	0.999
D759	8	0.995	0.999
D838	8	0.995	0.998
H863	8	0.995	0.999
S168	8	0.994	1.000
H665	8	0.994	0.998
H675	8	0.994	0.999
F871	8	0.994	1.000
F178	8	0.993	1.000
H715	8	0.993	0.998
H678	8	0.992	0.997
F812	8	0.991	1.000

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

4 prognostic cancer types:

Cancer	Prognostic	p-value
Ovary Serous Cystadenocarcinoma (TCGA)	unfavorable	0.000154
Glioblastoma Multiforme (validation)	favorable	0.000243
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	0.000336
Breast Invasive Carcinoma (validation)	favorable	0.000512

Disease associations

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

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
neurodevelopmental disorder with central hypotonia and dysmorphic facies	Strong	Autosomal dominant	4
2q37 microdeletion syndrome	Limited	Unknown

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (7 panels, 4 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

7 panels:

Panel	Rating
DDG2P	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Limb disorders	amber
Paediatric disorders	amber
Skeletal dysplasia	amber

Mondo (3): neurodevelopmental disorder with central hypotonia and dysmorphic facies (MONDO:0859232), 2q37 microdeletion syndrome (MONDO:0010886), plasma cell myeloma (MONDO:0009693)

Orphanet (3): 2q37 microdeletion syndrome (Orphanet:1001), Multiple myeloma (Orphanet:29073), AL amyloidosis (Orphanet:85443)

HPO phenotypes

showing 60 of 113 phenotypes (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
HP:0000708	Atypical behavior
HP:0000717	Autism
HP:0000718	Aggressive behavior
HP:0000722	Compulsive behaviors
HP:0000729	Autistic behavior
HP:0000733	Motor stereotypy
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0000768	Pectus carinatum
HP:0000776	Congenital diaphragmatic hernia
HP:0000821	Hypothyroidism
HP:0000964	Eczematoid dermatitis
HP:0001156	Brachydactyly
HP:0001187	Hyperextensibility of the finger joints
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0001344	Absent speech
HP:0001374	Congenital hip dislocation
HP:0001382	Joint hypermobility
HP:0001442	Typified by somatic mosaicism
HP:0001476	Delayed closure of the anterior fontanelle
HP:0001513	Obesity
HP:0001537	Umbilical hernia
HP:0001601	Laryngomalacia
HP:0001643	Patent ductus arteriosus

GWAS associations

24 associations:

Study	Trait	p-value
GCST001548_1	Male-pattern baldness	1e-12
GCST007576_214	Chronotype	1e-12
GCST001248_10	Pulmonary function	2e-12
GCST006988_51	Blond vs. brown/black hair color	2e-11
GCST006979_297	Heel bone mineral density	6e-10
GCST007505_23	Nevus count or cutaneous melanoma	1e-9
GCST006627_90	Diastolic blood pressure	4e-9
GCST007243_1	Intra-individual response time variability (selective attention)	3e-8
GCST007243_2	Intra-individual response time variability (selective attention)	3e-8
GCST010989_194	Body size at age 10	3e-8
GCST006010_5	Mean arterial pressure	5e-8
GCST001251_4	Pulmonary function	1e-7
GCST001784_24	Pulmonary function (smoking interaction)	2e-7
GCST007706_82	Mean arterial pressure	2e-7
GCST005051_10	Obstructive sleep apnea trait (apnea hypopnea index)	7e-7
GCST007704_93	Diastolic blood pressure	7e-7
GCST007504_6	Nevus count	8e-7
GCST007703_58	Systolic blood pressure	2e-6
GCST010578_1	CV-A6-associated hand, foot, and mouth disease (severe vs mild)	5e-6
GCST004250_3	Alanine aminotransferase (ALT) levels after remission induction therapy in actute lymphoblastic leukemia (ALL)	7e-6
GCST004792_4	Amyotrophic lateral sclerosis in C9orf72 mutation positive individuals	7e-6
GCST001877_73	Autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia (combined)	8e-6
GCST002892_10	Perioperative myocardial infarction in coronary artery bypass surgery	8e-6
GCST007649_6	Estimated glomerular filtration rate after 5 years in renal transplantation (recipient effect)	8e-6

EFO canonical traits (from GWAS)

16 canonical traits:

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

2 disease descriptors:

Descriptor	Name	Tree numbers
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

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 473,926 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

31 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL408513	BELINOSTAT	4	8,184
CHEMBL487253	BENDAMUSTINE	4	31,460
CHEMBL118	CELECOXIB	4	113,751
CHEMBL1213492	GIVINOSTAT	4	2,960
CHEMBL483254	PANOBINOSTAT	4	12,172
CHEMBL1469	PHENYLBUTANOIC ACID	4	37,412
CHEMBL343448	ROMIDEPSIN	4	13,626
CHEMBL1746	SODIUM PHENYLBUTYRATE	4	5,678
CHEMBL98	VORINOSTAT	4	51,304
CHEMBL2103863	ABEXINOSTAT	3	2,290
CHEMBL145	CAFFEIC ACID	3	36,727
CHEMBL140	CURCUMIN	3	95,185
CHEMBL27759	ENTINOSTAT	3	6,811
CHEMBL1851943	PRACINOSTAT	3	2,099
CHEMBL235191	TACEDINALINE	3	2,995
CHEMBL2107784	TASQUINIMOD	3	1,304
CHEMBL3621988	TUCIDINOSTAT	3	2,280
CHEMBL191482	AR-42	2	2,146
CHEMBL284616	CHLOROGENIC ACID	2	42,390
CHEMBL356066	DACINOSTAT	2	3,152
CHEMBL3622533	FIMEPINOSTAT	2
CHEMBL1801250	NANATINOSTAT	2
CHEMBL2105763	QUISINOSTAT	2
CHEMBL2364628	RICOLINOSTAT	2
CHEMBL3989941	TINOSTAMUSTINE	2
CHEMBL3287255	BISTHIANOSTAT	1
CHEMBL598797	CUDC-101	1
CHEMBL96	GAMMA-AMINOBUTYRIC ACID	1
CHEMBL353581	PYROXAMIDE	1
CHEMBL609583	R-306465	1
CHEMBL99	TRICHOSTATIN	1

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — 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)

2990 measured of 3637 human assays (3686 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
GNF-Pf-1011	IC50	0.001 nM
CHEMBL6148436	IC50	0.031 nM
CHEMBL4237803	KI	0.075 nM
N-[(1S)-1-[5-(2-fluorophenyl)-1H-imidazol-2-yl]-7-(1,2-oxazol-3-yl)-7-oxoheptyl]-1-methylazetidine-3-carboxamide	IC50	0.08 nM	US-12331044: Inhibitors of histone deacetylase useful for the treatment or prevention of HIV infection
JNJ-26481585	IC50	0.1 nM
Quinolone-based HDAC inhibitor 4i	IC50	0.1 nM
CHEMBL113303	IC50	0.11 nM
CHEMBL3622726	IC50	0.12 nM
4sc-202	IC50	0.16 nM
CHEMBL5218660	IC50	0.16 nM
CHEMBL4532398	IC50	0.19 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
CHEMBL1793991	IC50	0.2 nM
CHEMBL3126833	IC50	0.2 nM
CHEMBL4241370	KI	0.27 nM
CHEMBL1836142	IC50	0.28 nM
(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
CHEMBL5199116	IC50	0.3 nM
CHEMBL5170036	IC50	0.3 nM
CHEMBL5433552	IC50	0.34 nM
CHEMBL2158745	IC50	0.4 nM
CHEMBL6133389	IC50	0.4 nM
CHEMBL5395502	IC50	0.43 nM
HC toxin	KI	0.44 nM
CHEMBL3828518	IC50	0.45 nM
CHEMBL3218562	IC50	0.48 nM
CHEMBL3827517	IC50	0.55 nM
CHEMBL99392	KI	0.6 nM
CHEMBL3827814	IC50	0.65 nM
(6S,9S,12S,14aR)-6-((S)-sec-Butyl)-9-(1-methoxy-1H-indol-3-ylmethyl)-12-(6-oxo-octyl)-decahydro-4a,7,10,13-tetraaza-benzocyclododecene-5,8,11,14-tetraone	IC50	0.7 nM
(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
(3S,14S,15S)-6-Ethylidene-12-((R)-isopropyl)-3-isopropyl-16-(4-mercapto-but-1-enyl)-9-mercaptomethyl-1-oxa-4,7,10,13-tetraaza-cyclohexadecane-2,5,8,11,14-pentaone	IC50	0.8 nM
(S)-N8-hydroxy-2-(2-(5-methoxy-2-methyl-1H-indol-3-yl)acetamido)-N1-(2-(2-phenyl-1H-indol-3-yl)ethyl)octanediamide	IC50	0.8 nM
CHEMBL4592929	IC50	0.918 nM
CHEMBL3218563	IC50	0.94 nM
HDAC inhibitor, Compound 1	IC50	1 nM
CHEMBL3310505	IC50	1 nM
CHEMBL3758184	IC50	1 nM
CHEMBL3827281	IC50	1 nM
CHEMBL3827894	IC50	1 nM
CHEMBL1793823	IC50	1 nM
CHEMBL1793947	IC50	1 nM
CHEMBL4467135	IC50	1 nM
CHEMBL4080164	IC50	1.1 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
CHEMBL1836145	IC50	1.2 nM
CHEMBL4444219	IC50	1.2 nM
CHEMBL4794499	IC50	1.2 nM

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

2478 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
7-(5-bromo-2-oxo-3H-indol-1-yl)-N-hydroxyheptanamide	2237987: Inhibition of HDAC in human HeLa cells nuclear extract	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

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	affects cotreatment, decreases expression, increases methylation	4
Estradiol	affects binding, increases expression	3
bisphenol A	affects cotreatment, affects methylation, decreases methylation, increases expression	2
Cisplatin	decreases expression, decreases response to substance, increases activity	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	affects binding, decreases reaction	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

7 cell lines: 6 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_F5D1	EDITGENE HDAC4 Knockout HAP1 Cell Line	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)

Via MONDO — disease-level, not drug-specific.

showing 60 of 206 trials:

NCT	Phase	Status	Title
NCT05657860	Phase 4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	Phase 4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	Phase 4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	Phase 4	RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	Phase 3	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	Phase 2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	Phase 2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	Phase 2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	Phase 2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	Phase 1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	Phase 1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	Phase 1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	Phase 1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	Phase 1	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	Phase 2/3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	Phase 1/2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	Early Phase 1	TERMINATED	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
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NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
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NCT02934854	Not specified	WITHDRAWN	Biomarker for Creatine Deficiency Syndromes (BioCDS)
NCT03033797	Not specified	UNKNOWN	Augmentative and Alternative Communication in Games With Virtual Reality in Intellectual Disabilities
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NCT03203226	Not specified	COMPLETED	The Feldenkrais Method for People With Intellectual Disability
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NCT03234231	Not specified	UNKNOWN	Supervised Brushing Programme for Intellectual Disabled Students
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NCT03424772	Not specified	UNKNOWN	Whole Genome Sequencing in the Detection of Rare Undiagnosed Genetic Diseases in Children in China
NCT03426059	Not specified	COMPLETED	Mapping the Phenotype in Adults With Phelan-McDermid Syndrome
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NCT03501914	Not specified	COMPLETED	A Pilot Trial of Mindfulness Based Intervention Program for People With Intellectual Disabilities in a Low Income Setting
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Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for HDAC4 across ~30M SureChEMBL compounds — explore on Sugi Predict.