HDAC8

Summary

HDAC8 (histone deacetylase 8, HGNC:13315) is a protein-coding gene on chromosome Xq13.1, encoding Histone deacetylase 8 (Q9BY41). Histone deacetylase that catalyzes the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). It is haploinsufficient (ClinGen: sufficient evidence).

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 I of the histone deacetylase family. It catalyzes the deacetylation of lysine residues in the histone N-terminal tails and represses transcription in large multiprotein complexes with transcriptional co-repressors. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 55869 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Cornelia de Lange syndrome (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 467 total — 45 pathogenic, 51 likely-pathogenic
• Phenotypes (HPO): 136
• Druggable target: yes — 37 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_018486

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13315
Approved symbol	HDAC8
Name	histone deacetylase 8
Location	Xq13.1
Locus type	gene with protein product
Status	Approved
Aliases	RPD3, KDAC8
Ensembl gene	ENSG00000147099
Ensembl biotype	protein_coding
OMIM	300269
Entrez	55869

Gene structure

Transcript identifiers

Ensembl transcripts: 69 — 39 protein_coding, 20 nonsense_mediated_decay, 5 protein_coding_CDS_not_defined, 5 retained_intron

ENST00000373554, ENST00000373556, ENST00000373559, ENST00000373560, ENST00000373568, ENST00000373571, ENST00000373573, ENST00000373583, ENST00000373589, ENST00000412342, ENST00000415409, ENST00000421523, ENST00000436675, ENST00000439122, ENST00000444609, ENST00000470998, ENST00000478743, ENST00000486704, ENST00000647594, ENST00000647606, ENST00000647641, ENST00000647654, ENST00000647718, ENST00000647859, ENST00000647886, ENST00000647974, ENST00000647980, ENST00000648036, ENST00000648101, ENST00000648139, ENST00000648158, ENST00000648276, ENST00000648285, ENST00000648298, ENST00000648452, ENST00000648459, ENST00000648504, ENST00000648577, ENST00000648711, ENST00000648731, ENST00000648834, ENST00000648850, ENST00000648855, ENST00000648870, ENST00000648939, ENST00000648962, ENST00000649097, ENST00000649116, ENST00000649181, ENST00000649242, ENST00000649274, ENST00000649518, ENST00000649543, ENST00000649752, ENST00000650076, ENST00000650126, ENST00000650471, ENST00000650477, ENST00000650604, ENST00000650636, ENST00000881225, ENST00000881226, ENST00000881227, ENST00000881228, ENST00000881229, ENST00000881230, ENST00000925427, ENST00000958735, ENST00000958736

RefSeq mRNA: 11 — MANE Select: NM_018486 NM_001166418, NM_001166419, NM_001166420, NM_001166422, NM_001166448, NM_001410725, NM_001410727, NM_001410728, NM_001410729, NM_001410730, NM_018486

CCDS: CCDS14420, CCDS55448, CCDS55449, CCDS55450, CCDS55451, CCDS55452, CCDS94630, CCDS94631, CCDS94632, CCDS94633, CCDS94634

Canonical transcript exons

ENST00000373573 — 11 exons

Exon	Start	End
ENSE00001859665	72329516	72330076
ENSE00003473605	72488933	72489041
ENSE00003514348	72568754	72568884
ENSE00003540538	72567889	72568030
ENSE00003546080	72572057	72572109
ENSE00003552342	72490929	72491006
ENSE00003573968	72572651	72572843
ENSE00003600963	72351733	72351838
ENSE00003612797	72495156	72495268
ENSE00003644641	72462004	72462098
ENSE00003677170	72464559	72464731

Expression profiles

Bgee: expression breadth ubiquitous, 244 present calls, max score 91.85.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.2654 / max 107.3570, expressed in 1749 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199593	8.2654	1749

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
colonic epithelium	UBERON:0000397	91.85	gold quality
adrenal tissue	UBERON:0018303	90.76	gold quality
left adrenal gland	UBERON:0001234	90.33	gold quality
left adrenal gland cortex	UBERON:0035825	90.32	gold quality
right adrenal gland	UBERON:0001233	90.17	gold quality
tendon of biceps brachii	UBERON:0008188	90.09	gold quality
right adrenal gland cortex	UBERON:0035827	90.09	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.78	gold quality
adrenal gland	UBERON:0002369	89.68	gold quality
calcaneal tendon	UBERON:0003701	89.40	gold quality
cerebellar hemisphere	UBERON:0002245	89.34	gold quality
cerebellar cortex	UBERON:0002129	89.25	gold quality
adrenal cortex	UBERON:0001235	89.13	gold quality
adenohypophysis	UBERON:0002196	89.06	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.98	gold quality
Brodmann (1909) area 9	UBERON:0013540	88.97	gold quality
cerebellum	UBERON:0002037	88.46	gold quality
ganglionic eminence	UBERON:0004023	88.44	gold quality
islet of Langerhans	UBERON:0000006	88.15	gold quality
bone marrow cell	CL:0002092	88.14	gold quality
tendon	UBERON:0000043	87.88	gold quality
stromal cell of endometrium	CL:0002255	87.86	gold quality
anterior cingulate cortex	UBERON:0009835	87.69	gold quality
pituitary gland	UBERON:0000007	87.55	gold quality
sural nerve	UBERON:0015488	87.54	gold quality
hypothalamus	UBERON:0001898	87.30	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	87.30	gold quality
right frontal lobe	UBERON:0002810	87.03	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	87.00	gold quality
right ovary	UBERON:0002118	86.78	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-3929	yes	206.91
E-ANND-3	yes	7.91

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SOX4

miRNA regulators (miRDB)

23 targeting HDAC8, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-410-3P	99.27	69.98	2457
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-4511	98.32	67.97	1500
HSA-MIR-4654	95.86	65.72	751

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• PKA-mediated phosphorylation of HDAC8 plays a central role in the overall acetylation status of histones. (PMID:14701748)
• crystal structure (PMID:15477595)
• The HDAC8, another class I HDAC, was not detected in epithelial cells but was uniquely expressed in the cytoplasm of stromal cells. (PMID:15590418)
• findings indicate that histone deacetylase 8(HDAC8) associates with the smooth muscle actin cytoskeleton and may regulate the contractile capacity of smooth muscle cells (PMID:15772115)
• Identification of the in vivo metal ion of HDAC8 is essential for understanding the biological function and regulation of HDAC8 and for the development of improved inhibitors of this class of enzymes (PMID:16681389)
• HDAC8 regulation of hEST1B protein stability modulates total telomerase enzymatic activity (PMID:16809764)
• The crucial role of Asp 101 in substrate and inhibitor recognition was confirmed by activity and binding assays of wild-type HDAC8 and Asp101Ala, Tyr306Phe and Asp101Ala/Tyr306Phe mutants. (PMID:17721440)
• High expression of HDAC8 is associated with cancer tissues (PMID:17786334)
• HDAC8-selective inhibitors have a unique mechanism of action involving PLCgamma1 activation and calcium-induced apoptosis (PMID:18256683)
• analysis of human histone deacetylase 8 and its site-specific variants complexed with substrate and inhibitors (PMID:19053282)
• Expression of recombinant HDAC8 results in decreased CREB activation and CREB mediated gene transcription in response to forskolin application. (PMID:19070599)
• Our data point toward an important role of HDAC8 in neuroblastoma pathogenesis (PMID:19118036)
• recent developments in the crystal structure analysis of human HDAC4, HDAC7, and HDAC8 recent developments in the crystal structure analysis of human HDAC4, HDAC7, and HDAC8 [REVIEW] (PMID:19355988)
• it is likely that potassium is the predominant monovalent cations bound to HDAC8 in vivo. (PMID:20029090)
• HDAC8 could bind either or both Fe(2+) or Zn(2+) in vivo. (PMID:20545365)
• overexpression of HDAC1, 6 or 8 increased invasion and MMP-9 expression in breast cancer cells (PMID:21455583)
• Presented is the 2.14 A-resolution crystal structure of the HDAC8-largazole thiol complex. (PMID:21790156)
• Histone deacetylase 8 is required for centrosome cohesion and influenza A virus entry. (PMID:22046129)
• our data uncover a regulatory mechanism of mutant p53 transcription via HDAC8 (PMID:22391568)
• loss of HDAC8 activity results in increased SMC3 acetylation and inefficient dissolution of the ‘used’ cohesin complex released from chromatin in both prophase and anaphase (PMID:22885700)
• This family study showa that HDAC8 is involved in a syndromic form of intellectual disability. (PMID:22889856)
• Data indicate prominent changes in urothelial cancer cell lines (UCC) were HDAC2 and/or HDAC8 up-regulation. (PMID:22944197)
• Data indicate that knockdown of HDAC8 resulted in the increased expression of SOCS1 and SOCS3, and overexpression of SOCS1 and SOCS3 significantly inhibited cell growth and suppressed JAK2/STAT signaling. (PMID:23111066)
• HDAC8 plays an important role in the modulation of SOCS1 and SOCS3 by curcumin. (PMID:23430957)
• SOX4 is a direct target gene of FRA-2 and induces expression of HDAC8 in adult T-cell leukemia/lymphoma. (PMID:23482931)
• HDAC8 isoverexpressed in hepatocellular carcinoma; knockdown suppresses tumor growth and enhances apoptosis (PMID:24077923)
• Using molecular dynamics simulations the study found a mechanism whereby the interactions and dynamics of two loops tune the configuration of functionally important residues of HDAC8 and could therefore influence the activity of the enzyme. (PMID:24171457)
• Loss-of-function mutations in HDAC8 cause a range of overlapping phenotypic spectrum of Cornelia de Lange syndrome-like feature. (PMID:24403048)
• DEC1 coordinates with HDAC8 to differentially regulate TAp73 and DeltaNp73 expression. (PMID:24404147)
• In response to contractile stimulation, HDAC8 may mediate cortactin deacetylation, which subsequently promotes actin filament polymerization and smooth muscle contraction. (PMID:24920679)
• Deregulation of HDAC8 is frequent in urothelial cancer, but neither specific pharmacological inhibition nor siRNA-mediated knockdown of HDAC8 impaired viability of urothelial cancer cell lines in a therapeutic useful manner. (PMID:25011684)
• HDAC8 X-ray crystal structures reveal that each Cornelia de Lange syndrome mutation causes local structural changes that compromise catalysis and/or thermostability. (PMID:25075551)
• On the corresponding BMF gene promoter, loss of HDAC8 was associated with signal transducer and activator of transcription 3 (STAT3)/specificity protein 3 (Sp3) transcription factor exchange and recruitment of p300. (PMID:25321483)
• detailed thermodynamic studies of the binding of structurally similar ligands, which differed with respect to the “cap”, “linker”, and “metal-binding” regions of the suberoylanilide hydroxamic acid pharmacophore, to HDAC8 (PMID:25407689)
• histone deacetylase 8 inhibition reduces gene expression and production of proinflammatory cytokines in vitro and in vivo (PMID:25451941)
• Data reveal a role for miR-21-3p in regulating HDAC8 expression and Akt/Gsk3beta pathway in cardiac hypertrophy. (PMID:25504627)
• Studied the kinetics, thermodynamics, and selectivity of Zn(II) and Fe(II) binding to HDAC8. (PMID:25516458)
• Our mechanistic and cellular studies on HDAC8 activation have the potential to provide insight into the development of novel anticancer drugs. (PMID:25605725)
• report the X-ray crystal structures of HDAC8 complexed with three synthetic analogues of Largazole in which the depsipeptide ester is replaced with a rigid amide linkage (PMID:25793284)
• HDAC8 was increased in BRAF-mutated melanoma. Increased cytoplasmic HDAC8 immunoreactivity was independently associated with an improved survival from both diagnosis of primary melanoma and from first detection of stage IV disease to melanoma death (PMID:25836739)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	hdac8	ENSDARG00000003021
mus_musculus	Hdac8	ENSMUSG00000067567
rattus_norvegicus	Hdac8	ENSRNOG00000003122
caenorhabditis_elegans		WBGENE00009657
caenorhabditis_elegans		WBGENE00009663
caenorhabditis_elegans		WBGENE00219378

Paralogs (10): HDAC9 (ENSG00000048052), HDAC7 (ENSG00000061273), HDAC4 (ENSG00000068024), HDAC6 (ENSG00000094631), HDAC10 (ENSG00000100429), HDAC5 (ENSG00000108840), HDAC1 (ENSG00000116478), HDAC11 (ENSG00000163517), HDAC3 (ENSG00000171720), HDAC2 (ENSG00000196591)

Protein

Protein identifiers

Histone deacetylase 8 — Q9BY41 (reviewed: Q9BY41)

Alternative names: Protein deacetylase HDAC8, Protein decrotonylase HDAC8

All UniProt accessions (39): Q9BY41, A0A3B3IRI9, A0A3B3IRJ3, A0A3B3IRJ8, A0A3B3IRP8, A0A3B3IRZ0, A0A3B3IRZ8, A0A3B3IS08, A0A3B3IS37, A0A3B3IS68, A0A3B3IS93, A0A3B3ISB8, A0A3B3ISE4, A0A3B3ISG7, A0A3B3ISJ4, A0A3B3ISN6, A0A3B3ISP0, A0A3B3ISS7, A0A3B3ISY0, A0A3B3IT04, A0A3B3IT30, A0A3B3IT84, A0A3B3IT95, A0A3B3IT98, A0A3B3ITV2, A0A3B3ITZ3, A0A3B3IU01, A0A3B3IU21, A0A3B3IU52, A0A3B3IU62, A0A3B3IUD1, A6NFW1, A6NGJ7, A6NGT0, A6NMT1, C9J8F0, E7EVA8, E7EW22, F8WCG4

UniProt curated annotations — full annotation on UniProt →

Function. Histone deacetylase that catalyzes 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. Also involved in the deacetylation of cohesin complex protein SMC3 regulating release of cohesin complexes from chromatin. May play a role in smooth muscle cell contractility. In addition to protein deacetylase activity, also has protein-lysine deacylase activity: acts as a protein decrotonylase by mediating decrotonylation ((2E)-butenoyl) of histones.

Subunit / interactions. Interacts with PEPB2-MYH11, a fusion protein consisting of the 165 N-terminal residues of CBF-beta (PEPB2) with the tail region of MYH11 produced by the inversion Inv(16)(p13q22), a translocation associated with acute myeloid leukemia of M4EO subtype. The PEPB2-MYH1 fusion protein also interacts with RUNX1, a well known transcriptional regulator, suggesting that the interaction with HDAC8 may participate in the conversion of RUNX1 into a constitutive transcriptional repressor. Interacts with CBFA2T3. Interacts with phosphorylated SMG5/EST1B; this interaction protects SMG5 from ubiquitin-mediated degradation. Associates with alpha-SMA (smooth muscle alpha-actin).

Subcellular location. Nucleus. Chromosome. Cytoplasm.

Tissue specificity. Weakly expressed in most tissues. Expressed at higher level in heart, brain, kidney and pancreas and also in liver, lung, placenta, prostate and kidney.

Post-translational modifications. Phosphorylated by PKA on serine 39. Phosphorylation reduces deacetylase activity observed preferentially on histones H3 and H4.

Disease relevance. Cornelia de Lange syndrome 5 (CDLS5) [MIM:300882] A form of Cornelia de Lange syndrome, a clinically heterogeneous developmental disorder associated with malformations affecting multiple systems. It is characterized by facial dysmorphisms, abnormal hands and feet, growth delay, cognitive retardation, hirsutism, gastroesophageal dysfunction and cardiac, ophthalmologic and genitourinary anomalies. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Its activity is inhibited by trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA), 3-(1-methyl-4-phenylacetyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamide (APHA), 4-dimethylamino-N-(6-hydroxycarbamoyethyl)benzamide-N-hydroxy-7-(4-dimethylaminobenzoyl)aminoheptanamide (MS-344), 5-(4-methyl-benzoylamino)-biphenyl-3,4’-dicarboxylic acid 3-dimethylamide 4’-hydroxyamide (CRA-A) and butyrate.

Cofactor. Binds 1 divalent metal cation per subunit.

Similarity. Belongs to the histone deacetylase family. HD type 1 subfamily.

Isoforms (6)

UniProt ID	Names	Canonical?
Q9BY41-1	1	yes
Q9BY41-4	4
Q9BY41-5	5
Q9BY41-6	6
Q9BY41-7	7
Q9BY41-8	8

RefSeq proteins (11): NP_001159890, NP_001159891, NP_001159892, NP_001159894, NP_001159920, NP_001397654, NP_001397656, NP_001397657, NP_001397658, NP_001397659, NP_060956* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000286	HDACs	Family
IPR003084	HDAC_I/II	Family
IPR023696	Ureohydrolase_dom_sf	Homologous_superfamily
IPR023801	His_deacetylse_dom	Domain
IPR037138	His_deacetylse_dom_sf	Homologous_superfamily

Pfam: PF00850

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), 3 shown:

• N(6)-acetyl-L-lysyl-[protein] + H2O = L-lysyl-[protein] + acetate (RHEA:58108)
• N(6)-acetyl-L-lysyl-[histone] + H2O = L-lysyl-[histone] + acetate (RHEA:58196)
• N(6)-(2E)-butenoyl-L-lysyl-[protein] + H2O = (2E)-2-butenoate + L-lysyl-[protein] (RHEA:69172)

UniProt features (72 total): strand 15, helix 15, splice variant 9, mutagenesis site 9, turn 7, binding site 6, sequence variant 4, sequence conflict 3, chain 1, region of interest 1, active site 1, modified residue 1

Structure

Experimental structures (PDB)

53 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5VI6	X-RAY DIFFRACTION	1.24
5DC8	X-RAY DIFFRACTION	1.3
5D1C	X-RAY DIFFRACTION	1.42
7JVU	X-RAY DIFFRACTION	1.5
5DC6	X-RAY DIFFRACTION	1.55
5BWZ	X-RAY DIFFRACTION	1.59
4QA5	X-RAY DIFFRACTION	1.76
4RN0	X-RAY DIFFRACTION	1.76
3EW8	X-RAY DIFFRACTION	1.8
7JVV	X-RAY DIFFRACTION	1.84
3MZ4	X-RAY DIFFRACTION	1.84
5THV	X-RAY DIFFRACTION	1.87
1T64	X-RAY DIFFRACTION	1.9
3MZ7	X-RAY DIFFRACTION	1.9
5THS	X-RAY DIFFRACTION	1.9
4QA1	X-RAY DIFFRACTION	1.92
5DC5	X-RAY DIFFRACTION	1.94
5THU	X-RAY DIFFRACTION	1.95
5FCW	X-RAY DIFFRACTION	1.98
4QA4	X-RAY DIFFRACTION	1.98
2V5W	X-RAY DIFFRACTION	2
3MZ6	X-RAY DIFFRACTION	2
3SFF	X-RAY DIFFRACTION	2
5D1D	X-RAY DIFFRACTION	2.01
4QA6	X-RAY DIFFRACTION	2.05
6HSK	X-RAY DIFFRACTION	2.1
3RQD	X-RAY DIFFRACTION	2.14
4RN1	X-RAY DIFFRACTION	2.18
1VKG	X-RAY DIFFRACTION	2.2
4QA0	X-RAY DIFFRACTION	2.24

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BY41-F1	95.45	0.93

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): 143 (proton acceptor)

Ligand- & substrate-binding residues (6): 101; 151; 178; 180; 267; 306

Post-translational modifications (1): 39

Mutagenesis-validated functional residues (9):

Position	Phenotype
39	enhances the deacetylase activity.
39	decreases the deacetylase activity.
101	complete loss of catalytical activity. complete loss of catalytical activity; when associated with f-306.
101	partial loss of catalytical activity.
101	complete loss of catalytical activity.
101	almost complete loss of catalytical activity.
142–143	strongly reduces histone deacetylase activity.
143	loss of catalytic activity.
306	loss of catalytic activity. complete loss of catalytic activity; when associated with a-101.

Function

Pathways and Gene Ontology

Reactome pathways

8 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-3214815	HDACs deacetylate histones
R-HSA-350054	Notch-HLH transcription pathway
R-HSA-9976102	Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)
R-HSA-2467813	Separation of Sister Chromatids
R-HSA-2500257	Resolution of Sister Chromatid Cohesion

MSigDB gene sets: 460 (showing top): PID_HDAC_CLASSI_PATHWAY, GOBP_CHROMOSOME_ORGANIZATION, REACTOME_SIGNALING_BY_NOTCH, GOBP_TELOMERE_ORGANIZATION, ACTGCAG_MIR173P, GGGTGGRR_PAX4_03, AAAYRNCTG_UNKNOWN, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_REGULATION_OF_TELOMERE_MAINTENANCE, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, GOBP_SISTER_CHROMATID_COHESION, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_REGULATION_OF_PROTEIN_STABILITY, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_METABOLIC_PROCESS, GOBP_REGULATION_OF_CHROMOSOME_ORGANIZATION

GO Biological Process (7): negative regulation of transcription by RNA polymerase II (GO:0000122), chromatin organization (GO:0006325), mitotic sister chromatid cohesion (GO:0007064), negative regulation of protein ubiquitination (GO:0031397), heterochromatin formation (GO:0031507), regulation of protein stability (GO:0031647), regulation of telomere maintenance (GO:0032204)

GO Molecular Function (11): histone deacetylase activity (GO:0004407), Hsp70 protein binding (GO:0030544), protein lysine deacetylase activity (GO:0033558), metal ion binding (GO:0046872), Hsp90 protein binding (GO:0051879), DNA-binding transcription factor binding (GO:0140297), histone deacetylase activity, hydrolytic mechanism (GO:0141221), histone decrotonylase activity (GO:0160009), protein binding (GO:0005515), hydrolase activity (GO:0016787), protein decrotonylase activity (GO:0160008)

GO Cellular Component (6): histone deacetylase complex (GO:0000118), nuclear chromosome (GO:0000228), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Signaling by NOTCH1	1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1
Chromatin modifying enzymes	1
Generic Transcription Pathway	1
Differentiation of T cells	1
Mitotic Anaphase	1
Mitotic Prometaphase	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
histone modifying activity	2
heat shock protein binding	2
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides	2
nuclear lumen	2
cellular anatomical structure	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
cellular component organization	1
sister chromatid cohesion	1
protein ubiquitination	1
regulation of protein ubiquitination	1
negative regulation of protein modification by small protein conjugation or removal	1
cellular component assembly	1
heterochromatin boundary formation	1
negative regulation of gene expression, epigenetic	1
heterochromatin organization	1
regulation of biological quality	1
telomere maintenance	1
regulation of chromosome organization	1
regulation of DNA metabolic process	1
protein lysine deacetylase activity	1
protein-folding chaperone binding	1
deacetylase activity	1
catalytic activity, acting on a protein	1
cation binding	1
transcription factor binding	1
histone deacetylase activity	1
protein decrotonylase activity	1
binding	1
catalytic activity	1
nucleoplasm	1
nuclear protein-containing complex	1
catalytic complex	1
nucleus	1
chromosome	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

2999 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HDAC8	RBBP4	P31149	917
HDAC8	SIN3A	Q96ST3	905
HDAC8	MORF4L1	Q9UBU8	892
HDAC8	SIRT2	Q8IXJ6	874
HDAC8	NIPBL	Q6KC79	862
HDAC8	SIRT1	Q96EB6	856
HDAC8	SMC3	Q9UQE7	838
HDAC8	SMG5	Q9UPR3	819
HDAC8	SUDS3	Q9H7L9	805
HDAC8	SMC1A	Q14683	797
HDAC8	SMAD3	P84022	791
HDAC8	EZH2	Q15910	782
HDAC8	SAP30	O75446	779
HDAC8	H3C14	Q71DI3	774
HDAC8	H3-5	Q6NXT2	774
HDAC8	H3-4	Q16695	774

IntAct

7 interactions, top by confidence:

A	B	Type	Score
TP53	HDAC8	psi-mi:“MI:0407”(direct interaction)	0.440
XPO7	HDAC8	psi-mi:“MI:0915”(physical association)	0.400
HDAC8	STAT3	psi-mi:“MI:0915”(physical association)	0.400
Xpo7	HAT1	psi-mi:“MI:0914”(association)	0.350
HDAC8	SEC16A	psi-mi:“MI:0914”(association)	0.350
	HDAC8	psi-mi:“MI:0914”(association)	0.350

BioGRID (81): HDAC8 (Affinity Capture-Western), HDAC8 (Affinity Capture-Western), VPRBP (Affinity Capture-Western), DDB1 (Affinity Capture-Western), HDAC8 (Affinity Capture-MS), HDAC8 (Affinity Capture-RNA), HDAC8 (Protein-peptide), HDAC8 (Affinity Capture-MS), HDAC8 (Negative Genetic), TSC2 (Negative Genetic), HDAC8 (Negative Genetic), TSC1 (Negative Genetic), TRAPPC11 (Negative Genetic), IGF2BP1 (Negative Genetic), SLC30A5 (Negative Genetic)

ESM2 similar proteins: A2VE14, A5PLN9, B1WC68, D3Z7P3, O54865, O89050, O94925, P13264, P16068, P20595, P38024, P51583, P97834, Q02153, Q0VCB2, Q0VCJ8, Q13042, Q13098, Q3TIR1, Q4R4U1, Q4ZHR9, Q5F450, Q5M887, Q5NVN7, Q5R5F8, Q5RB35, Q5RB59, Q5RBN9, Q5RKN4, Q5ZJB7, Q5ZMH6, Q67FW5, Q6AXQ0, Q6NRT5, Q86TJ2, Q8R349, Q8VH37, Q91YQ7, Q99LD4, Q99PV3

Diamond homologs: B1H369, B1WC68, O09106, O13298, O15379, O17695, O22446, O30107, O42227, O59702, O88895, P32561, P39067, P53096, P56517, P56518, P56519, P56520, P56521, P56524, P70288, P83038, Q02959, Q09440, Q0VCB2, Q12214, Q13547, Q28DV3, Q32PJ8, Q3JUN4, Q4QQW4, Q4SFA0, Q54X15, Q55BW2, Q55FN5, Q5R902, Q5RAG0, Q5RB76, Q6GPA7, Q6IRL9

SIGNOR signaling

20 interactions.

A	Effect	B	Mechanism
PRKACA	down-regulates	HDAC8	phosphorylation
N-hydroxy-1-[(4-methoxyphenyl)methyl]-6-indolecarboxamide	down-regulates	HDAC8	“chemical inhibition”
4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide	down-regulates	HDAC8	“chemical inhibition”
(S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide	“down-regulates activity”	HDAC8	“chemical inhibition”
HDAC8	“up-regulates quantity by stabilization”	SMG5	binding
HDAC8	“down-regulates activity”	TP53	deacetylation
belinostat	“down-regulates activity”	HDAC8	“chemical inhibition”
panobinostat	“down-regulates activity”	HDAC8	“chemical inhibition”
JWOGUUIOCYMBPV-GMFLJSBRSA-N	“down-regulates activity”	HDAC8	“chemical inhibition”
vorinostat	“down-regulates activity”	HDAC8	“chemical inhibition”
N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide	“down-regulates activity”	HDAC8	“chemical inhibition”
“trichostatin A”	“down-regulates activity”	HDAC8	“chemical inhibition”
“N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester”	“down-regulates activity”	HDAC8	“chemical inhibition”
romidepsin	“down-regulates activity”	HDAC8	“chemical inhibition”
6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide	“down-regulates activity”	HDAC8	“chemical inhibition”
CUDC-101	“down-regulates activity”	HDAC8	“chemical inhibition”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	45
Likely pathogenic	51
Uncertain significance	122
Likely benign	122
Benign	38

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1072722	NM_018486.3(HDAC8):c.164+2dup	Pathogenic
1076180	NM_018486.3(HDAC8):c.522C>G (p.Tyr174Ter)	Pathogenic
1164056	NM_018486.3(HDAC8):c.471T>G (p.Asp157Glu)	Pathogenic
1323053	NM_018486.3(HDAC8):c.75_82del (p.Val25_Ser26insTer)	Pathogenic
1333326	NM_018486.3(HDAC8):c.881G>A (p.Trp294Ter)	Pathogenic
1417489	NM_018486.3(HDAC8):c.956C>T (p.Thr319Ile)	Pathogenic
158658	NM_018486.3(HDAC8):c.131del (p.Ser43_Leu44insTer)	Pathogenic
1701604	NM_018486.3(HDAC8):c.581_582del (p.Lys194fs)	Pathogenic
1742375	NM_018486.3(HDAC8):c.467A>G (p.Asn156Ser)	Pathogenic
2029945	NM_018486.3(HDAC8):c.748del (p.Glu250fs)	Pathogenic
211139	NM_018486.3(HDAC8):c.134_137del (p.Ile45fs)	Pathogenic
211141	NM_018486.3(HDAC8):c.229C>T (p.Gln77Ter)	Pathogenic
2426477	NC_000023.10:g.(?71681834)(71681968_?)del	Pathogenic
2445981	NM_018486.3(HDAC8):c.75_82dup (p.Cys28fs)	Pathogenic
2500631	NM_018486.3(HDAC8):c.211C>T (p.His71Tyr)	Pathogenic
265658	NM_018486.3(HDAC8):c.907G>T (p.Gly303Ter)	Pathogenic
2691318	NM_018486.3(HDAC8):c.1010dup (p.Thr338fs)	Pathogenic
280671	NM_018486.3(HDAC8):c.787C>T (p.Gln263Ter)	Pathogenic
280793	NM_018486.3(HDAC8):c.496C>T (p.Arg166Ter)	Pathogenic
3237489	NM_018486.3(HDAC8):c.550+1G>T	Pathogenic
3245515	NC_000023.10:g.(?71571563)(71571708_?)del	Pathogenic
3245526	NC_000023.10:g.(?71710759)(71715138_?)del	Pathogenic
3524475	NM_018486.3(HDAC8):c.193G>T (p.Glu65Ter)	Pathogenic
3602918	NM_018486.3(HDAC8):c.910+1G>A	Pathogenic
37252	NM_018486.3(HDAC8):c.164+5G>A	Pathogenic
3898875	NM_018486.3(HDAC8):c.910+1G>T	Pathogenic
39710	NM_018486.3(HDAC8):c.490C>T (p.Arg164Ter)	Pathogenic
39711	NM_018486.3(HDAC8):c.539A>G (p.His180Arg)	Pathogenic
39714	NM_018486.3(HDAC8):c.1001A>G (p.His334Arg)	Pathogenic
419411	NM_018486.3(HDAC8):c.165-2A>G	Pathogenic

SpliceAI

2424 predictions. Top by Δscore:

Variant	Effect	Δscore
X:72351727:GCTCA:G	donor_loss	1.0000
X:72351728:CTCA:C	donor_loss	1.0000
X:72351729:TCA:T	donor_loss	1.0000
X:72351730:CAC:C	donor_loss	1.0000
X:72351834:AAAAA:A	acceptor_gain	1.0000
X:72351835:AAAA:A	acceptor_gain	1.0000
X:72351836:AAA:A	acceptor_gain	1.0000
X:72351837:AA:A	acceptor_gain	1.0000
X:72351839:C:CC	acceptor_gain	1.0000
X:72351841:G:C	acceptor_gain	1.0000
X:72495149:GGCTT:G	donor_loss	1.0000
X:72495152:TTA:T	donor_loss	1.0000
X:72495153:TACC:T	donor_loss	1.0000
X:72495154:A:AC	donor_gain	1.0000
X:72495154:A:AG	donor_loss	1.0000
X:72495155:C:CC	donor_gain	1.0000
X:72495155:CCAT:C	donor_gain	1.0000
X:72567887:A:AC	donor_gain	1.0000
X:72567888:C:CC	donor_gain	1.0000
X:72567888:CTT:C	donor_gain	1.0000
X:72567931:TTGC:T	donor_gain	1.0000
X:72568032:T:C	acceptor_gain	1.0000
X:72568756:AG:A	donor_gain	1.0000
X:72568756:AGC:A	donor_gain	1.0000
X:72568757:G:C	donor_gain	1.0000
X:72568880:CTATC:C	acceptor_gain	1.0000
X:72568881:TATC:T	acceptor_gain	1.0000
X:72568883:TC:T	acceptor_gain	1.0000
X:72568883:TCC:T	acceptor_loss	1.0000
X:72568884:CC:C	acceptor_gain	1.0000

AlphaMissense

2476 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:72495250:A:C	F152L	1.000
X:72495250:A:T	F152L	1.000
X:72495252:A:G	F152L	1.000
X:72462066:A:G	W315R	0.999
X:72462066:A:T	W315R	0.999
X:72462071:C:G	R313P	0.999
X:72462074:G:T	A312D	0.999
X:72464669:T:A	D267V	0.999
X:72464670:C:G	D267H	0.999
X:72464687:A:T	V261D	0.999
X:72489035:C:T	G212D	0.999
X:72490933:G:C	F208L	0.999
X:72490933:G:T	F208L	0.999
X:72490935:A:G	F208L	0.999
X:72490936:A:C	F207L	0.999
X:72490936:A:T	F207L	0.999
X:72490938:A:G	F207L	0.999
X:72490956:G:C	H201D	0.999
X:72490962:A:G	S199P	0.999
X:72490990:G:C	F189L	0.999
X:72490990:G:T	F189L	0.999
X:72490991:A:G	F189S	0.999
X:72490992:A:G	F189L	0.999
X:72495161:C:T	G182E	0.999
X:72495168:G:C	H180D	0.999
X:72495172:A:C	D178E	0.999
X:72495172:A:T	D178E	0.999
X:72495173:T:A	D178V	0.999
X:72495173:T:G	D178A	0.999
X:72495188:A:G	L173P	0.999

dbSNP variants (sampled 300 via entrez): RS1000014819 (X:72512685 C>G,T), RS1000026818 (X:72362491 C>G), RS1000033231 (X:72440544 T>A,G), RS1000095715 (X:72373302 T>C), RS1000164679 (X:72471069 T>A,C,G), RS1000165045 (X:72370787 C>G), RS1000180831 (X:72337069 T>C), RS1000191605 (X:72539689 G>C), RS1000205719 (X:72510503 G>C), RS1000219191 (X:72540281 T>C), RS1000223059 (X:72481082 A>G), RS1000254701 (X:72550114 G>A), RS1000295194 (X:72480639 A>G), RS1000347905 (X:72412075 G>A), RS1000351583 (X:72570896 C>A,T)

Disease associations

OMIM: gene MIM:300269 | disease phenotypes: MIM:300882, MIM:122470, MIM:108800, MIM:173900

GenCC curated gene-disease

Disease	Classification	Inheritance
Cornelia de Lange syndrome 5	Definitive	X-linked
Cornelia de Lange syndrome	Supportive	Autosomal dominant
Wilson-Turner syndrome	Supportive	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Cornelia de Lange syndrome	Definitive	XL

Mondo (10): neurodevelopmental disorder (MONDO:0700092), Cornelia de Lange syndrome 5 (MONDO:0010471), microcephaly (MONDO:0001149), fetal growth restriction (MONDO:0005030), Cornelia de Lange syndrome 1 (MONDO:0007387), intellectual disability (MONDO:0001071), atrial septal defect (MONDO:0006664), polycystic kidney disease (MONDO:0020642), Cornelia de Lange syndrome (MONDO:0016033), Wilson-Turner syndrome (MONDO:0010665)

Orphanet (3): Cornelia de Lange syndrome (Orphanet:199), Interatrial communication (Orphanet:1478), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

136 total (30 of 136 shown, HPO-id order):

HPO	Term
HP:0000003	Multicystic kidney dysplasia
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000059	Hypoplastic labia majora
HP:0000076	Vesicoureteral reflux
HP:0000083	Renal insufficiency
HP:0000130	Abnormality of the uterus
HP:0000135	Hypogonadism
HP:0000175	Cleft palate
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000233	Thin vermilion border
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000294	Low anterior hairline
HP:0000316	Hypertelorism
HP:0000336	Prominent supraorbital ridges
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000400	Macrotia
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000413	Atresia of the external auditory canal
HP:0000426	Prominent nasal bridge
HP:0000453	Choanal atresia

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST006030_19	Chloride levels	8.000000e-21
GCST006032_1	Sodium levels	6.000000e-35
GCST012466_5	Autism spectrum disorder	6.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009282	sodium measurement

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D005317	Fetal Growth Retardation	C12.050.703.277.370; C16.300.390; C23.550.393.450
D006344	Heart Septal Defects, Atrial	C14.240.400.560.375; C14.280.400.560.375; C16.131.240.400.560.375
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
D065886	Neurodevelopmental Disorders	F03.625
D007690	Polycystic Kidney Diseases	C12.050.351.968.419.403.875; C12.200.777.419.403.875; C12.950.419.403.875; C16.131.077.717; C16.320.184.625
C536708	Wilson-Turner X-linked mental retardation syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (8): CHEMBL2093865 (PROTEIN FAMILY), CHEMBL3038483 (PROTEIN FAMILY), CHEMBL3192 (SINGLE PROTEIN), CHEMBL3885589 (PROTEIN FAMILY), CHEMBL4523988 (PROTEIN FAMILY), CHEMBL5465222 (PROTEIN-PROTEIN INTERACTION), CHEMBL5465240 (PROTEIN-PROTEIN INTERACTION), CHEMBL6195591 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

37 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 637,748 (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
CHEMBL178	DAUNORUBICIN	4	203,756
CHEMBL325041	BORTEZOMIB	4	13,120
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
CHEMBL1801250	NANATINOSTAT	2	754
CHEMBL191482	AR-42	2	2,061
CHEMBL284616	CHLOROGENIC ACID	2
CHEMBL356066	DACINOSTAT	2
CHEMBL3622533	FIMEPINOSTAT	2
CHEMBL14227	BUTYRIC ACID	2
CHEMBL2105763	QUISINOSTAT	2
CHEMBL2364628	RICOLINOSTAT	2
CHEMBL272980	MOCETINOSTAT	2
CHEMBL3693786	CITARINOSTAT	2
CHEMBL62381	SODIUM BUTYRATE	2
CHEMBL8260	BAICALEIN	2

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 (26 total), top 25:

Ligand	Action	Affinity	Parameter
romidepsin	Inhibition	9.82	pKi
compound 25ap [PMID: 37796543]	Inhibition	9.8	pIC50
quisinostat	Inhibition	8.37	pIC50
trichostatin A	Inhibition	8.35	pKi
SZUH280	Inhibition	8.0	pKi
givinostat	Inhibition	7.41	pKi
CUDC-101	Inhibition	7.1	pIC50
ricolinostat	Inhibition	7.0	pIC50
scriptaid	Inhibition	6.98	pKi
citarinostat	Inhibition	6.86	pIC50
J27644	Inhibition	6.82	pIC50
marbostat-100	Inhibition	6.76	pKi
vorinostat	Inhibition	6.69	pKi
belinostat	Inhibition	6.67	pEC50
panobinostat	Inhibition	6.61	pEC50
dacinostat	Inhibition	6.47	pKi
KA1010	Inhibition	6.44	pIC50
suprastat	Inhibition	6.3	pIC50
apicidin	Inhibition	6.24	pEC50
tubastatin A	Inhibition	6.09	pIC50
resminostat	Inhibition	6.06	pIC50
SS-208	Inhibition	5.91	pIC50
droxinostat	Inhibition	5.84	pIC50
compound 11 [PMID: 41150938]	Inhibition	5.44	pIC50
BML-281	Inhibition	5.09	pIC50

Binding affinities (BindingDB)

377 measured of 405 human assays (412 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
(E)-3-[4-[(1-adamantylmethylamino)methyl]phenyl]-N-hydroxyprop-2-enamide	IC50	0.95 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
(E)-3-[4-[(cyclohexylmethylamino)methyl]-3-fluorophenyl]-N-hydroxyprop-2-enamide	IC50	1.64 nM	US-10188756: Imaging histone deacetylases with a radiotracer using positron emission tomography
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
triazole-linked clarithromycin-based compound, 24d	IC50	1.9 nM
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
2-hydroxy-6-isopropyl-cyclohepta-2,4,6-trien-1-one	KI	3.32 nM	US-9790158: Substituted tropolone derivatives and methods of use
triazole-linked clarithromycin-based compound, 24c	IC50	4.1 nM
(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
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
(E)-3-[4-[[cyclohexylmethyl(methyl)amino]methyl]-3-fluorophenyl]-N-hydroxyprop-2-enamide	IC50	5.43 nM	US-10188756: Imaging histone deacetylases with a radiotracer using positron emission tomography
R-TSA	IC50	5.76 nM
6-cyclopentyl-2-hydroxycyclohepta-2,4,6-trien-1-one	KI	6.64 nM	US-9790158: Substituted tropolone derivatives and methods of use
3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide	KI	7 nM
HDAC inhibitor, Compound 2	IC50	7.93 nM
Quinolone-based HDAC inhibitor 4o	IC50	10 nM
HDAC inhibitor, Compound 1	IC50	10.1 nM
7-{4-[4-({(2S,3R,4S,6R)-2-{[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl]oxy}-3-hydroxy-6-methyloxan-4-ylamino}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-N-hydroxyheptanamide	IC50	10.6 nM
triazole-linked azithromycin-based compound, 16c	IC50	13.9 nM
N-[3-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl]-N’-hydroxyoctanediamide	IC50	14.5 nM
N-(3-{1-[2-(3-bromophenyl)-2-hydroxyethyl]-1H-1,2,3-triazol-4-yl}phenyl)-N’-hydroxyoctanediamide	IC50	14.9 nM
Bendamustine	IC50	17 nM	US-9096627: Hydroxamic acid derivatives
N-(3-{1-[(4-fluorophenyl)methyl]-1H-1,2,3-triazol-4-yl}phenyl)-N’-hydroxyoctanediamide	IC50	17.6 nM
(E)-N-hydroxy-3-[3-[methyl(phenyl)sulfamoyl]phenyl]prop-2-enamide	IC50	17.8 nM	US-10188756: Imaging histone deacetylases with a radiotracer using positron emission tomography
N-hydroxy-N’-[3-(1-phenyl-1H-1,2,3-triazol-4-yl)phenyl]octanediamide	IC50	18 nM
N-[3-(1-benzyl-1H-1,2,3-triazol-5-yl)phenyl]-N’-hydroxyoctanediamide	IC50	18.6 nM
(2E,4E,6R)-7-[4-(dimethylamino)phenyl]-N-hydroxy-4,6-dimethyl-7-oxohepta-2,4-dienamide	IC50	19 nM
N-(3-{1-[2-(3-bromophenyl)-2-hydroxyethyl]-1H-1,2,3-triazol-5-yl}phenyl)-N’-hydroxyoctanediamide	IC50	23.4 nM
(E)-3-[3-[(1-adamantylamino)methyl]phenyl]-N-hydroxyprop-2-enamide	IC50	24 nM	US-10188756: Imaging histone deacetylases with a radiotracer using positron emission tomography
N-(3-{1-[(4-fluorophenyl)methyl]-1H-1,2,3-triazol-5-yl}phenyl)-N’-hydroxyoctanediamide	IC50	25.9 nM
2-(5-methoxy-2-methyl-1H-indol-3-yl)-N-[(1S)-7-oxo-1-(5-phenyl-1H-imidazol-2-yl)nonyl]acetamide	IC50	26 nM
N-hydroxy-N’-[4-(1-phenyl-1H-1,2,3-triazol-4-yl)phenyl]octanediamide	IC50	27.1 nM
Quinolone-based HDAC inhibitor 4p	IC50	28 nM
Quinolone-based HDAC inhibitor 4r	IC50	28 nM
Quinolone-based HDAC inhibitor 4a	IC50	32 nM
Quinolone-based HDAC inhibitor 4k	IC50	32 nM

ChEMBL bioactivities

6100 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.40	Ki	0.04	nM	CHEMBL2408241
10.00	Ki	0.1	nM	OXAMFLATIN
9.99	IC50	0.103	nM	CHEMBL6174035
9.92	IC50	0.12	nM	CHEMBL5595114
9.85	Ki	0.14	nM	CHEMBL2408239
9.82	Ki	0.15	nM	ROMIDEPSIN
9.77	IC50	0.17	nM	CHEMBL5433552
9.77	Ki	0.17	nM	CHEMBL2408237
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
9.60	IC50	0.25	nM	APICIDIN
9.60	IC50	0.253	nM	TRICHOSTATIN
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
9.46	IC50	0.35	nM	VORINOSTAT
9.43	IC50	0.37	nM	CHEMBL98245
9.40	IC50	0.4	nM	CHEMBL2371000
9.40	IC50	0.4	nM	CHEMBL1793816
9.39	IC50	0.41	nM	CHEMBL4441774
9.39	IC50	0.407	nM	CHEMBL6173928
9.36	Ki	0.44	nM	CHEMBL2408240
9.32	IC50	0.473	nM	CHEMBL6172024
9.30	Ki	0.5	nM	QUISINOSTAT
9.29	IC50	0.511	nM	CHEMBL6145619
9.28	Ki	0.53	nM	CHEMBL2408237
9.24	IC50	0.575	nM	CHEMBL6133082
9.12	IC50	0.753	nM	CHEMBL6169315
9.10	IC50	0.8	nM	CHEMBL4534486
9.10	IC50	0.8	nM	CHEMBL5632276
9.10	IC50	0.791	nM	VORINOSTAT
9.08	IC50	0.83	nM	PANOBINOSTAT
9.05	IC50	0.9	nM	CHEMBL605110
9.02	IC50	0.95	nM	CHEMBL595479
9.00	IC50	1	nM	CHEMBL3758184
9.00	IC50	1	nM	APICIDIN
9.00	IC50	1	nM	CHEMBL2371003
9.00	IC50	1	nM	ROMIDEPSIN
9.00	IC50	1	nM	CHEMBL4467135
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

PubChem BioAssay actives

2698 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
(E)-5-[4-(benzenesulfonamido)phenyl]-N-hydroxypent-2-en-4-ynamide	1236445: Inhibition of human HDAC8	ki	0.0001	uM
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
(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
(5R,8S,11S)-11-[(Z)-2-fluoro-4-sulfanylbut-1-enyl]-5-methyl-8-propan-2-yl-10-oxa-3,17-dithia-7,14,19,20-tetrazatricyclo[14.2.1.12,5]icosa-1(18),2(20),16(19)-triene-6,9,13-trione	1566041: Inhibition of full length C-terminal His-tagged human HDAC8 expressed in baculovirus infected Sf9 cells using Ac-peptide-AMC as substrate preincubated for 15 mins followed by substrate addition and measured after 240 mins by fluorescence based assay	ic50	0.0004	uM
2-hydroxy-3-phenylcyclohepta-2,4,6-trien-1-one	760379: Competitive inhibition of human recombinant HDAC8 by Michaelis-Menten equation analysis	ki	0.0005	uM
N-hydroxy-2-[4-[[(1-methylindol-3-yl)methylamino]methyl]piperidin-1-yl]pyrimidine-5-carboxamide	1236445: Inhibition of human HDAC8	ki	0.0005	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’-[(5-bromothiophen-2-yl)methyl]-N-hydroxy-N’-[4-(2-morpholin-4-ylethoxy)phenyl]heptanediamide	1927785: Inhibition of HDAC8 (unknown origin)	ic50	0.0011	uM
(2R)-N-[4-[1-[7-(hydroxyamino)-7-oxoheptyl]-4-morpholin-4-ylpyrazolo[5,4-d]pyrimidin-6-yl]phenyl]-2-methylmorpholine-4-carboxamide	1614129: Inhibition of recombinant full length C-terminal His-tagged human HDAC8 expressed in baculovirus expression system using Ac-peptide-AMC as substrate preincubated for 15 mins followed by substrate addition and measured after 1 hr by fluorescence assay	ic50	0.0013	uM
7-[6-(5-fluoro-6-methoxy-3-pyridinyl)-4-methylquinazolin-8-yl]oxy-N-hydroxyheptanamide	2127736: Inhibition of HDAC8 (unknown origin)	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
2-hydroxy-6-phenylcyclohepta-2,4,6-trien-1-one	760388: Inhibition of human recombinant HDAC8 by Michaelis-Menten equation analysis	ki	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
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
6-[(2,6-dimethoxy-4-methylquinolin-8-yl)carbamoylamino]oxy-N-hydroxyhexanamide	1938398: Inhibition of HDAC8 (unknown origin)	ic50	0.0017	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
N-hydroxy-7-[5-(4-methoxyphenyl)-1,3-oxazol-2-yl]heptanamide	316872: Inhibition of HDAC from human K562 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
N-[6-(2-fluorophenyl)-1H-indazol-3-yl]-N’-hydroxyoctanediamide	1737135: Inhibition of recombinant human full length C-terminal His-tagged HDAC8 expressed in sf9 insect cells using Boc-Lys(TFA)-AM as substrate incubated for 60 mins by fluorescence assay	ic50	0.0024	uM
N-hydroxy-7-[3-[4-[[(7-hydroxy-21-methyl-14-oxo-3,13,21-triazapentacyclo[11.8.0.02,10.04,9.015,20]henicosa-2(10),4(9),5,7,15(20),16,18-heptaen-17-yl)amino]methyl]phenyl]-1,2,4-oxadiazol-5-yl]heptanamide	1225981: Inhibition of recombinant C-terminal His-tagged full length human HDAC8 expressed in baculovirus infected insect Sf9 cells using fluorogenic HDAC class 2a substrate after 30 mins by fluorescence assay	ic50	0.0025	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	2127942: Inhibition of HDAC8 (unknown origin) incubated for 30 mins by ELISA	ic50	0.0029	uM
7-[4-[[5-chloro-4-(4-fluoroanilino)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	0.0030	uM
7-[4-[[5-chloro-4-(4-methoxyanilino)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	0.0030	uM
7-[4-[[5-fluoro-4-(4-fluoroanilino)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	0.0030	uM
N-[(1S)-1-[5-(2-fluorophenyl)-1H-imidazol-2-yl]-7-(1,2-oxazol-3-yl)-7-oxoheptyl]-1-methylazetidine-3-carboxamide	1664944: Inhibition of human recombinant HDAC8 expressed in Escherichia coli using FLUOR DE LYS as substrate preincubated for 3 hrs followed by substrate addition and measured after 60 mins by fluorescence based assay	ic50	0.0030	uM
(2S)-2-[5-(2-cyclopropylethynyl)-4-(3,5-dimethoxyphenyl)triazol-1-yl]-N-hydroxy-3-phenylpropanamide	1631200: Inhibition of HDAC8 (unknown origin) using fluorophore-conjugated substrate by fluorescence assay	ic50	0.0030	uM
7-[5-chloro-2-hydroxy-3-(3-nitroso-1H-indol-2-yl)indol-1-yl]-N-hydroxyheptanamide	1697196: Inhibition of HDAC in human HeLa nuclear extract using fluoroscence-labeled acetylated peptide as substrate by fluorometric assay	ic50	0.0030	uM
N’-hydroxy-N-[6-(3-methoxyphenyl)-1H-indazol-3-yl]octanediamide	1737135: Inhibition of recombinant human full length C-terminal His-tagged HDAC8 expressed in sf9 insect cells using Boc-Lys(TFA)-AM as substrate incubated for 60 mins by fluorescence assay	ic50	0.0030	uM
(1S,4S,7S,10S)-7,10-dibenzyl-4-[6-(oxiran-2-yl)-6-oxohexyl]-3,6,9-triazabicyclo[10.4.0]hexadecane-2,5,8,11-tetrone	1927177: Binding affinity to HDAC8 (unknown origin) assessed as dissociation constant by ITC analysis	kd	0.0030	uM
2-[[2-(4-aminophenyl)-9-methyl-6-morpholin-4-ylpurin-8-yl]methyl-methylamino]-N-hydroxypyrimidine-5-carboxamide	1312867: Inhibition of HDAC in human HeLa cell nuclear extract using Ac-Leu-Gly-Lys (Ac)-AMC as substrate after 30 mins by fluorescence assay	ic50	0.0032	uM
7-[4-(4-chloroanilino)-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	0.0032	uM
N-[6-(3,4-dimethoxyphenyl)-1H-indazol-3-yl]-N’-hydroxyoctanediamide	1737135: Inhibition of recombinant human full length C-terminal His-tagged HDAC8 expressed in sf9 insect cells using Boc-Lys(TFA)-AM as substrate incubated for 60 mins by fluorescence assay	ic50	0.0032	uM
(E)-3-[4-[2-(1,2-dimethylindol-3-yl)ethylsulfamoyl]phenyl]-N-hydroxyprop-2-enamide	1187258: Inhibition of HDAC in human HeLa cells nuclear extracts incubated for 30 mins by fluorescent assay	ic50	0.0033	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression	6
bisphenol A	increases expression, increases methylation, affects cotreatment, decreases expression	3
bisphenol S	decreases methylation, affects cotreatment, decreases expression	2
Vorinostat	affects cotreatment, decreases expression, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Estradiol	affects expression, decreases expression	2
aristolochic acid I	decreases expression	1
selenomethylselenocysteine	decreases reaction, increases expression, affects binding	1
beta-lapachone	decreases expression	1
arsenite	affects binding, increases reaction	1
malealdehyde	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
aflatoxin B2	decreases methylation	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
glycidamide	increases expression	1
pentabromodiphenyl ether	decreases expression	1
monomethylarsonous acid	affects cotreatment, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
octanedioic acid (1-(3-azido-5-azidomethylbenzyl)-1H-pyrazol-4-yl)amide hydroxyamide	affects binding, decreases activity	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases activity	1
Resveratrol	affects cotreatment, increases expression	1
Arsenic Trioxide	increases expression	1
Fulvestrant	increases methylation	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Berberine	decreases expression	1
Cobalt	affects binding	1

ChEMBL screening assays

2631 unique, capped per target: 2599 binding, 25 admet, 6 functional, 1 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

10 cell lines: 5 cancer cell line, 3 embryonic stem cell, 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A2M8	SEES3-1V human HDAC8, clone1	Embryonic stem cell	Male
CVCL_A2M9	SEES3-1V human HDAC8, clone2	Embryonic stem cell	Male
CVCL_A2N0	SEES3-1V human HDAC8, clone3	Embryonic stem cell	Male
CVCL_AW23	K562 eGFP-HDAC8	Cancer cell line	Female
CVCL_C0F8	SJTUXHi001-A	Induced pluripotent stem cell	Female
CVCL_C1WF	SDQLCHi046-A	Induced pluripotent stem cell	Male
CVCL_SR18	HAP1 HDAC8 (-) 1	Cancer cell line	Male
CVCL_SR19	HAP1 HDAC8 (-) 2	Cancer cell line	Male
CVCL_SR20	HAP1 HDAC8 (-) 3	Cancer cell line	Male
CVCL_SR21	HAP1 HDAC8 (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00347867	PHASE4	UNKNOWN	Viagra for the Treatment of IUGR
NCT00909974	PHASE4	COMPLETED	Effect of Prenatal Nutritional Supplementation on Birth Outcome in Hounde District, Burkina Faso
NCT01352234	PHASE4	COMPLETED	Comparison of Doses of Acetylsalicylic Acid in Women With Previous History of Preeclampsia
NCT01390051	PHASE4	COMPLETED	Can Low Molecular Weight Heparin During Pregnancy With Intrauterine Growth Restriction Increase Birth Weight?
NCT01695070	PHASE4	COMPLETED	Melatonin to Prevent Brain Injury in Unborn Growth Restricted Babies
NCT03674606	PHASE4	COMPLETED	Trial of Early Screening Test for Pre-eclampsia and Growth Restriction
NCT04051567	PHASE4	UNKNOWN	Low-dose Aspirin for Prevention of Adverse Pregnancy Outcomes in Twin Pregnancies
NCT05029778	PHASE4	UNKNOWN	Arginine + Citrulline as a Supplement for Weight Gain in Fetus With a Decrease in Their Growth Curve
NCT05800938	PHASE4	COMPLETED	The Effect of Oral Isosorbide Mononitrate Therapy on Umbilical Artery Doppler Resistance Index in Pregnancies With Intrauterine Growth Restriction: Prospective Randomized Control Trial
NCT07171086	PHASE4	NOT_YET_RECRUITING	AI-POCUS for Maternal and Neonatal Health in Ethiopia
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT00174252	PHASE3	COMPLETED	Study Aimed At Improving Height With Genotonorm In Children Born Little And/Or Light With Growth Retardation At The Age
NCT00197340	PHASE3	COMPLETED	Antepartum Chronic Epidural Therapy (ACET) to Improve Blood Flow to the Uterus, Placenta and Baby in Pre-Eclampsia and Intrauterine Growth Restriction
NCT00452491	PHASE3	COMPLETED	MAXOMAT ® in the Treatment of Severe Early Onset Intrauterine Growth Retardation on Pre-pubertal Children
NCT01073605	PHASE3	COMPLETED	Genotropin Treatment in Short Prepubertal Children With Intra-Uterine Growth Retardation
NCT02336243	PHASE3	UNKNOWN	A Randomized Trial of Docosahexaenoic Acid Supplementation During Pregnancy to Prevent Deep Placentation Disorders
NCT02590536	PHASE3	COMPLETED	A Trial Evaluating the Role of Sildenafil in the Treatment of Fetal Growth Restriction
NCT02672566	PHASE3	COMPLETED	Low-molecular-weight Heparin in Constituted Vascular Intrauterine Growth Restriction
NCT03177824	PHASE3	UNKNOWN	Sildenafil Citrate for Treatment of Growth-restricted Fetuses
NCT03230162	PHASE3	UNKNOWN	Sildenafil Versus Low Molecular Weight Heparin in Fetal Growth Restriction Treatment
NCT03324139	PHASE3	COMPLETED	Treatment of Intrauterine Growth Restriction With Low Molecular Heparin.
NCT03669185	PHASE3	UNKNOWN	Pentaerithrityl Tetranitrate (PETN) for Secondary Prevention of Intrauterine Growth Restriction
NCT04084990	PHASE3	TERMINATED	Sleep Apnea and Fetal Growth Restriction
NCT04356326	PHASE3	RECRUITING	Chronic Hypertension and Acetyl Salicylic Acid in Pregnancy
NCT04557475	PHASE3	WITHDRAWN	Transplacental Aspirin Therapy for Early Onset Fetal Growth Restriction
NCT04762992	PHASE3	ENROLLING_BY_INVITATION	LMWH for Treatment of Early Fetal Growth Restriction (HepaGrowth)
NCT05253781	PHASE3	COMPLETED	Low Dose Aspirin for Preventing Intrauterine Growth Restriction and Preeclampsia in Sickle Cell Pregnancy (PIPSICKLE)
NCT05651347	PHASE3	RECRUITING	Antenatal Melatonin Supplementation for Neuroprotection in Fetal Growth Restriction
NCT05774236	PHASE3	COMPLETED	Cook´s Balloon Versus Dinoprostone for Labor Induction of Term Pregnancies With Fetal Growth Restriction
NCT06497959	PHASE3	RECRUITING	Study of Placental Vascularization Using Contrast Ultrasound
NCT04381897	PHASE2	NOT_YET_RECRUITING	Use of N-Acetylcysteine in the Treatment of Repetitive and Self-Injurious Behaviors in Cornelia de Lange Syndrome
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT02280031	PHASE2	COMPLETED	Effect of Low Dose Aspirin on Birthweight in Twins: The GAP Trial.