H4C11

Summary

H4C11 (H4 clustered histone 11, HGNC:4785) is a protein-coding gene on chromosome 6p22.1, encoding Histone H4 (P62805). Core component of nucleosome.

Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. This gene is intronless and encodes a replication-dependent histone that is a member of the histone H4 family. Transcripts from this gene lack polyA tails but instead contain a palindromic termination element. This gene is found in the small histone gene cluster on chromosome 6p22-p21.3.

Source: NCBI Gene 8363 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Tessadori-van Haaften neurodevelopmental syndrome 2 (Moderate, GenCC)
• GWAS associations: 18
• Clinical variants (ClinVar): 26 total — 1 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 23
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_021968

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4785
Approved symbol	H4C11
Name	H4 clustered histone 11
Location	6p22.1
Locus type	gene with protein product
Status	Approved
Aliases	H4/e, H4F2iv
Ensembl gene	ENSG00000197238
Ensembl biotype	protein_coding
OMIM	602826
Entrez	8363

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000355057

RefSeq mRNA: 1 — MANE Select: NM_021968 NM_021968

CCDS: CCDS4630

Canonical transcript exons

ENST00000355057 — 1 exons

Exon	Start	End
ENSE00001409947	27824092	27824480

Expression profiles

Bgee: expression breadth ubiquitous, 120 present calls, max score 98.80.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 176.5225 / max 6588.1464, expressed in 1809 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
66588	176.5225	1809

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bone marrow cell	CL:0002092	98.80	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.83	gold quality
colonic epithelium	UBERON:0000397	78.70	gold quality
mucosa of stomach	UBERON:0001199	72.25	gold quality
bone marrow	UBERON:0002371	71.54	gold quality
calcaneal tendon	UBERON:0003701	70.69	gold quality
lower esophagus mucosa	UBERON:0035834	66.60	gold quality
tonsil	UBERON:0002372	62.87	gold quality
ganglionic eminence	UBERON:0004023	61.59	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	61.42	gold quality
ventricular zone	UBERON:0003053	57.19	silver quality
skeletal muscle tissue	UBERON:0001134	54.78	gold quality
sural nerve	UBERON:0015488	53.51	silver quality
blood	UBERON:0000178	53.11	gold quality
cortical plate	UBERON:0005343	53.09	gold quality
vermiform appendix	UBERON:0001154	52.77	gold quality
uterine cervix	UBERON:0000002	52.30	gold quality
muscle tissue	UBERON:0002385	51.69	gold quality
placenta	UBERON:0001987	49.13	gold quality
liver	UBERON:0002107	48.31	gold quality
urinary bladder	UBERON:0001255	48.08	gold quality
endocervix	UBERON:0000458	47.32	gold quality
hindlimb stylopod muscle	UBERON:0004252	45.91	gold quality
cortex of kidney	UBERON:0001225	45.58	gold quality
smooth muscle tissue	UBERON:0001135	45.47	gold quality
primary visual cortex	UBERON:0002436	44.86	gold quality
kidney	UBERON:0002113	44.33	gold quality
right coronary artery	UBERON:0001625	44.13	gold quality
prefrontal cortex	UBERON:0000451	43.95	gold quality
lymph node	UBERON:0000029	42.34	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-56	yes	331.56
E-ANND-3	yes	4.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000111501
mus_musculus	H4c6	ENSMUSG00000069274
rattus_norvegicus	Hist1h4b	ENSRNOG00000067648

Paralogs (14): H4C8 (ENSG00000158406), H4C3 (ENSG00000197061), H4C16 (ENSG00000197837), H4C15 (ENSG00000270276), H4C14 (ENSG00000270882), H4C12 (ENSG00000273542), H4C6 (ENSG00000274618), H4C13 (ENSG00000275126), H4C7 (ENSG00000275663), H4C9 (ENSG00000276180), H4C5 (ENSG00000276966), H4C4 (ENSG00000277157), H4C1 (ENSG00000278637), H4C2 (ENSG00000278705)

Protein

Protein identifiers

Histone H4 — P62805 (reviewed: P62805)

All UniProt accessions (2): B2R4R0, P62805

UniProt curated annotations — full annotation on UniProt →

Function. Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.

Subunit / interactions. The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA. Found in a co-chaperone complex with DNJC9, MCM2 and histone H3.3-H4 dimers. Within the complex, interacts with DNJC9 (via C-terminus); the interaction is direct. Interacts with NASP; NASP is a histone chaperone that stabilizes and maintains a soluble pool of Histone H3-H4 dimers.

Subcellular location. Nucleus. Chromosome.

Post-translational modifications. Acetylation at Lys-6 (H4K5ac), Lys-9 (H4K8ac), Lys-13 (H4K12ac) and Lys-17 (H4K16ac) occurs in coding regions of the genome but not in heterochromatin. Acetylated as part of spermatogenesis progression prior to histone-to-protamine exchange. Citrullination at Arg-4 (H4R3ci) by PADI4 impairs methylation. Monomethylation and asymmetric dimethylation at Arg-4 (H4R3me1 and H4R3me2a, respectively) by PRMT1 favors acetylation at Lys-9 (H4K8ac) and Lys-13 (H4K12ac). Demethylation is performed by JMJD6. Symmetric dimethylation on Arg-4 (H4R3me2s) by the PRDM1/PRMT5 complex may play a crucial role in the germ-cell lineage. Monomethylated, dimethylated or trimethylated at Lys-21 (H4K20me1, H4K20me2, H4K20me3). Monomethylation is performed by KMT5A/SET8. Dimethylation and trimethylation is performed by KMT5B and KMT5C and induces gene silencing. Monomethylated at Lys-13 (H4K12me1) by N6AMT1; H4K12me1 modification is present at the promoters of numerous genes encoding cell cycle regulators. H4K20me2 and H4K20me3 are demethylated into monomethyl (H4K20me1) by RSBN1. H4K20me1, H4K20me2 and H4K20me3 are demethylated by RAD23A and RAD23B. H4K20me1 is demethylated by PHF8. Acetyl-methylated at Lys-6 and Lys-13 (H4K5acme and H4K12acme, respectively), acetyl-methylation is an epigenetic mark of active chromatin associated with increased transcriptional initiation. Acetyl-methylation is formed by acetylation by EP300/p300 of lysine residues that are already monomethylated on the same side chain. H4K5acme and H4K12acme marks specifically bind BRD2. Phosphorylated by PAK2 at Ser-48 (H4S47ph). This phosphorylation increases the association of H3.3-H4 with the histone chaperone HIRA, thus promoting nucleosome assembly of H3.3-H4 and inhibiting nucleosome assembly of H3.1-H4. Ubiquitinated by the CUL4-DDB-RBX1 complex in response to ultraviolet irradiation. This may weaken the interaction between histones and DNA and facilitate DNA accessibility to repair proteins. Monoubiquitinated at Lys-92 of histone H4 (H4K91ub1) in response to DNA damage. The exact role of H4K91ub1 in DNA damage response is still unclear but it may function as a licensing signal for additional histone H4 post-translational modifications such as H4 Lys-21 methylation (H4K20me). Ubiquitinated; by PHF7. Ufmylated; monofmylated by UFL1 at Lys-32 (H4K31Ufm1) in response to DNA damage. Sumoylated, which is associated with transcriptional repression. Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes. Butyrylation of histones marks active promoters and competes with histone acetylation. Glutarylation at Lys-92 (H4K91glu) destabilizes nucleosomes by promoting dissociation of the H2A-H2B dimers from nucleosomes. Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription. Delactylated by SIRT3 at Lys-17 (H4K16la).

Disease relevance. Tessadori-Bicknell-Van Haaften neurodevelopmental syndrome 1 (TEBIVANED1) [MIM:619758] An autosomal dominant disorder with onset in infancy, characterized by poor overall growth, microcephaly, hypotonia, profound global developmental delay, impaired intellectual development, poor or absent speech, and characteristic dysmorphic facial features, including hypertelorism and abnormal nose. Other variable neurologic and systemic features may also occur. The disease is caused by variants affecting the gene represented in this entry. TEBIVANED1 is caused by variants in H4C3. Tessadori-Bicknell-Van Haaften neurodevelopmental syndrome 2 (TEBIVANED2) [MIM:619759] An autosomal dominant disorder characterized by poor overall growth, microcephaly, hypotonia, profound global developmental delay, impaired intellectual development, absent speech, and characteristic dysmorphic facial features, including hypertelorism, abnormal nose, and wide mouth. The disease is caused by variants affecting the gene represented in this entry. TEBIVANED2 is caused by variants in H4C11. Tessadori-Bicknell-Van Haaften neurodevelopmental syndrome 3 (TEBIVANED3) [MIM:619950] An autosomal dominant disorder characterized by global developmental delay with poor overall growth, impaired intellectual development, and speech difficulties. More variable features include hypotonia, microcephaly, and dysmorphic facies. The disease is caused by variants affecting the gene represented in this entry. TEBIVANED3 is caused by variants in H4C5. Tessadori-Bicknell-Van Haaften neurodevelopmental syndrome 4 (TEBIVANED4) [MIM:619951] An autosomal dominant disorder characterized by global developmental delay with poor overall growth, variably impaired intellectual development, learning difficulties, distal skeletal anomalies, and dysmorphic facies. Some patients have visual or hearing deficits. The disease is caused by variants affecting the gene represented in this entry. TEBIVANED4 is caused by variants in H4C9. Chromosomal aberrations involving HISTONE H4 is a cause of B-cell non-Hodgkin lymphomas (B-cell NHL). Translocation t(3;6)(q27;p21), with BCL6.

Similarity. Belongs to the histone H4 family.

RefSeq proteins (1): NP_068803* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001951	Histone_H4	Family
IPR004823	TAF_TATA-bd_Histone-like_dom	Domain
IPR009072	Histone-fold	Homologous_superfamily
IPR019809	Histone_H4_CS	Conserved_site
IPR035425	CENP-T/H4_C	Domain

Pfam: PF15511

UniProt features (138 total): modified residue 94, sequence variant 17, cross-link 8, strand 4, helix 4, mutagenesis site 2, sequence conflict 2, turn 2, initiator methionine 1, chain 1, DNA-binding region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

626 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
3F9X	X-RAY DIFFRACTION	1.25
8PEF	X-RAY DIFFRACTION	1.28
5TEG	X-RAY DIFFRACTION	1.3
3UVW	X-RAY DIFFRACTION	1.37
8UK5	X-RAY DIFFRACTION	1.4
1ZKK	X-RAY DIFFRACTION	1.45
4YY6	X-RAY DIFFRACTION	1.45
3F9Y	X-RAY DIFFRACTION	1.5
3QZT	X-RAY DIFFRACTION	1.5
4YYI	X-RAY DIFFRACTION	1.5
4YYM	X-RAY DIFFRACTION	1.5
5FFW	X-RAY DIFFRACTION	1.5
2BQZ	X-RAY DIFFRACTION	1.5
4YYD	X-RAY DIFFRACTION	1.52
8B5C	X-RAY DIFFRACTION	1.58
6RXS	X-RAY DIFFRACTION	1.6
3F9W	X-RAY DIFFRACTION	1.6
3F9Z	X-RAY DIFFRACTION	1.6
6VO5	X-RAY DIFFRACTION	1.6
7M98	X-RAY DIFFRACTION	1.6
2IG0	X-RAY DIFFRACTION	1.7
3O36	X-RAY DIFFRACTION	1.7
4QUT	X-RAY DIFFRACTION	1.7
5YE3	X-RAY DIFFRACTION	1.7
4YYH	X-RAY DIFFRACTION	1.74
8TGP	X-RAY DIFFRACTION	1.76
4YYK	X-RAY DIFFRACTION	1.79
5YE4	X-RAY DIFFRACTION	1.8
3QZS	X-RAY DIFFRACTION	1.8
4QUU	X-RAY DIFFRACTION	1.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P62805-F1	90.90	0.75

Antibody-complex structures (SAbDab): 21 — 5YE3, 5YE4, 6E0C, 6E0P, 7K5X, 7K5Y, 7K60, 7K61, 7K63, 7U0G, 7U0I, 7U0J, 8DK5, 8EVG, 8EVH, 8EVI, 8EVJ, 8SPS, 8SPU, 8SYP, 8VFX

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (102): 4, 21, 32, 32, 60, 80, 92, 92, 6, 6, 6, 6, 6, 6, 6, 6, 9, 9, 9, 9 …

Mutagenesis-validated functional residues (2):

Position	Phenotype
13	impaired methylation by n6amt1.
32	abolished ufmylation.

Function

Pathways and Gene Ontology

Reactome pathways

60 pathways

ID	Pathway
R-HSA-110328	Recognition and association of DNA glycosylase with site containing an affected pyrimidine
R-HSA-110329	Cleavage of the damaged pyrimidine
R-HSA-110330	Recognition and association of DNA glycosylase with site containing an affected purine
R-HSA-110331	Cleavage of the damaged purine
R-HSA-1221632	Meiotic synapsis
R-HSA-171306	Packaging Of Telomere Ends
R-HSA-1912408	Pre-NOTCH Transcription and Translation
R-HSA-201722	Formation of the beta-catenin:TCF transactivating complex
R-HSA-212300	PRC2 methylates histones and DNA
R-HSA-2299718	Condensation of Prophase Chromosomes
R-HSA-2559580	Oxidative Stress Induced Senescence
R-HSA-2559582	Senescence-Associated Secretory Phenotype (SASP)
R-HSA-2559586	DNA Damage/Telomere Stress Induced Senescence
R-HSA-3214815	HDACs deacetylate histones
R-HSA-3214841	PKMTs methylate histone lysines
R-HSA-3214842	HDMs demethylate histones
R-HSA-3214847	HATs acetylate histones
R-HSA-3214858	RMTs methylate histone arginines
R-HSA-427359	SIRT1 negatively regulates rRNA expression
R-HSA-427389	ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression
R-HSA-427413	NoRC negatively regulates rRNA expression
R-HSA-4551638	SUMOylation of chromatin organization proteins
R-HSA-5250924	B-WICH complex positively regulates rRNA expression
R-HSA-5334118	DNA methylation
R-HSA-5578749	Transcriptional regulation by small RNAs
R-HSA-5617472	Activation of anterior HOX genes in hindbrain development during early embryogenesis
R-HSA-5625886	Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3
R-HSA-5693565	Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks
R-HSA-5693571	Nonhomologous End-Joining (NHEJ)
R-HSA-5693607	Processing of DNA double-strand break ends

MSigDB gene sets: 249 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, REACTOME_MEIOTIC_RECOMBINATION, GOBP_CHROMOSOME_ORGANIZATION, REACTOME_DNA_REPLICATION, REACTOME_SIGNALING_BY_NOTCH, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_MEIOTIC_SYNAPSIS, REACTOME_G2_M_DNA_DAMAGE_CHECKPOINT, GOBP_TELOMERE_ORGANIZATION, KONG_E2F3_TARGETS, REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS, GOBP_REGULATION_OF_HEMOPOIESIS, GOBP_PROTEIN_LOCALIZATION_TO_CHROMOSOME_CENTROMERIC_REGION, GOBP_PROTEIN_LOCALIZATION_TO_CHROMATIN, GOBP_REGULATION_OF_MEGAKARYOCYTE_DIFFERENTIATION

GO Biological Process (5): chromatin organization (GO:0006325), nucleosome assembly (GO:0006334), telomere organization (GO:0032200), negative regulation of megakaryocyte differentiation (GO:0045653), protein localization to CENP-A containing chromatin (GO:0061644)

GO Molecular Function (5): DNA binding (GO:0003677), RNA binding (GO:0003723), structural constituent of chromatin (GO:0030527), protein heterodimerization activity (GO:0046982), protein binding (GO:0005515)

GO Cellular Component (10): chromosome, telomeric region (GO:0000781), nucleosome (GO:0000786), extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), membrane (GO:0016020), protein-containing complex (GO:0032991), CENP-A containing nucleosome (GO:0043505), extracellular exosome (GO:0070062), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Chromatin modifying enzymes	5
Cellular Senescence	3
Depyrimidination	2
Depurination	2
Meiosis	1
Telomere Maintenance	1
Pre-NOTCH Expression and Processing	1
TCF dependent signaling in response to WNT	1
Epigenetic regulation of gene expression	1
Mitotic Prophase	1
Negative epigenetic regulation of rRNA expression	1
Positive epigenetic regulation of rRNA expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
nucleic acid binding	2
chromatin	2
cellular component organization	1
chromatin organization	1
nucleosome organization	1
protein-DNA complex assembly	1
chromosome organization	1
megakaryocyte differentiation	1
negative regulation of myeloid cell differentiation	1
regulation of megakaryocyte differentiation	1
protein localization to chromatin	1
protein localization to chromosome, centromeric region	1
structural molecule activity	1
protein dimerization activity	1
binding	1
chromosomal region	1
protein-DNA complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular_component	1
nucleosome	1
CENP-A containing chromatin	1
extracellular vesicle	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

672 interactions, top by confidence:

A	B	Type	Score
ASF1A	H4C16	psi-mi:“MI:0915”(physical association)	0.950
H4C16	ASF1A	psi-mi:“MI:0915”(physical association)	0.950
ASF1A	H4C16	psi-mi:“MI:0914”(association)	0.950
H3C1	H4C16	psi-mi:“MI:0915”(physical association)	0.890
H4C16	H3C1	psi-mi:“MI:0407”(direct interaction)	0.890
ASF1A	MCM2	psi-mi:“MI:0915”(physical association)	0.890
ASF1A	MCM2	psi-mi:“MI:0914”(association)	0.890
TP53BP1	H4C16	psi-mi:“MI:0407”(direct interaction)	0.870
H3-3A	H4C16	psi-mi:“MI:0915”(physical association)	0.860
H3-3A	H4C16	psi-mi:“MI:0914”(association)	0.860
H3-3A	H4C16	psi-mi:“MI:0407”(direct interaction)	0.860
H2AC4	H2BC11	psi-mi:“MI:0915”(physical association)	0.850

BioGRID (3544): RBBP4 (Affinity Capture-Western), HIST1H4A (Affinity Capture-Western), HIST4H4 (Biochemical Activity), HIST4H4 (Affinity Capture-MS), HIST2H4B (Affinity Capture-MS), HIST4H4 (Two-hybrid), ASF1A (Two-hybrid), HIST4H4 (Biochemical Activity), HIST4H4 (Biochemical Activity), HIST1H4I (Affinity Capture-RNA), HIST1H4E (Affinity Capture-RNA), HIST1H4I (Affinity Capture-RNA), HIST1H4E (Affinity Capture-RNA), HIST1H4E (Affinity Capture-RNA), HIST1H4A (Biochemical Activity)

ESM2 similar proteins: P02309, P08436, P09322, P0CG89, P23750, P23751, P27996, P35057, P35059, P50566, P59259, P62785, P62786, P62787, P62788, P62794, P62797, P62798, P62799, P62800, P62801, P62802, P62803, P62805, P62806, P62887, Q27443, Q27765, Q43083, Q4R362, Q5RCS7, Q6LAF1, Q6LAF3, Q6PMI5, Q6V9I2, Q6WV72, Q6WV73, Q6WV90, Q6WZ83, Q71V09

Diamond homologs: P02309, P04914, P04915, P08436, P09322, P0CG89, P23750, P23751, P27996, P35057, P35059, P50566, P59259, P62776, P62777, P62778, P62779, P62780, P62781, P62782, P62783, P62784, P62785, P62786, P62787, P62788, P62790, P62791, P62792, P62793, P62794, P62795, P62796, P62797, P62798, P62799, P62800, P62801, P62802, P62803

SIGNOR signaling

27 interactions.

A	Effect	B	Mechanism
TP53BP1	unknown	H4C1	binding
MAML1	“down-regulates activity”	H4C1	acetylation
“Integrator complex”	“down-regulates quantity by repression”	H4C1	“transcriptional regulation”
KAT5	“down-regulates activity”	H4C1	acetylation
H4C1	“up-regulates activity”	BRD2	relocalization
H4C1	“up-regulates activity”	BRD4	relocalization
H4C1	“up-regulates activity”	BRDT	relocalization
H4C1	“form complex”	“Nucleosome_H3.3 variant”	binding
“MSL acetyltransferase”	“down-regulates activity”	H4C1	acetylation
UFL1	“up-regulates activity”	H4C1	ubiquitination
SLBP	“up-regulates quantity by expression”	H4C1	“translation regulation”
“NSL histone acetyltransferase”	“down-regulates activity”	H4C1	acetylation
“NuA4 complex”	“down-regulates activity”	H4C1	acetylation
DTX3L	“down-regulates activity”	H4C1	monoubiquitination
“BRCA1-BARD1 complex”	“up-regulates activity”	H4C1	ubiquitination
H4C1	“form complex”	“CENP-A nucleosome”	binding
H4C1	“form complex”	“Nucleosome_H2A.Z.2 variant”	binding
H4C1	“form complex”	“Nucleosome_H2A.Z.1 variant”	binding
H4C1	“form complex”	“Nucleosome_H3.1 variant”	binding
H4C1	“form complex”	“Nucleosome_H3.1t variant”	binding
HAT1	“down-regulates activity”	H4C1	acetylation
H4C1	“form complex”	Nucleosome	binding
KMT5C	“down-regulates activity”	H4C1	methylation
KMT5B	“down-regulates activity”	H4C1	methylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 107 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
Formation of Senescence-Associated Heterochromatin Foci (SAHF)	5	40.5×	1e-06
Notch-HLH transcription pathway	6	29.5×	6e-07
NOTCH1 Intracellular Domain Regulates Transcription	8	22.9×	3e-08
ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression	12	22.0×	3e-11
Packaging Of Telomere Ends	8	21.2×	7e-08
FXIIa activates plasma kallikrein-kinin system	10	20.9×	2e-09
Condensation of Prophase Chromosomes	11	20.7×	3e-10
NuRD complex assembly	12	20.4×	7e-11

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of gene expression, epigenetic	6	25.3×	2e-05
nucleosome assembly	16	23.6×	5e-15
heterochromatin formation	8	21.5×	1e-06
epigenetic regulation of gene expression	5	20.2×	3e-04
chromatin organization	12	12.5×	9e-08
antimicrobial humoral immune response mediated by antimicrobial peptide	5	8.5×	1e-02
chromatin remodeling	11	8.4×	1e-05
DNA damage response	10	5.6×	6e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	2
Uncertain significance	17
Likely benign	4
Benign	2

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1342159	NM_021968.4(H4C11):c.274A>G (p.Lys92Glu)	Pathogenic
2681786	NM_021968.4(H4C11):c.106C>T (p.Arg36Trp)	Likely pathogenic
3235278	NM_021968.4(H4C11):c.295T>C (p.Tyr99His)	Likely pathogenic

SpliceAI

48 predictions. Top by Δscore:

Variant	Effect	Δscore
6:27824184:TA:T	donor_gain	0.7500
6:27824185:AA:A	donor_gain	0.7500
6:27824186:AA:A	donor_gain	0.7500
6:27824297:TGCTG:T	donor_gain	0.7200
6:27824431:G:GA	donor_gain	0.5700
6:27824148:G:GT	donor_gain	0.5500
6:27824323:A:AG	donor_gain	0.5200
6:27824182:C:G	donor_gain	0.5000
6:27824430:T:TA	donor_gain	0.5000
6:27824171:C:G	donor_gain	0.4700
6:27824168:GCGC:G	donor_gain	0.4600
6:27824148:G:T	donor_gain	0.4500
6:27824187:A:AG	donor_gain	0.4500
6:27824188:G:GG	donor_gain	0.4500
6:27824329:G:GT	donor_gain	0.4500
6:27824429:GTGGT:G	donor_gain	0.4400
6:27824284:G:GT	donor_gain	0.4200
6:27824183:G:GG	donor_gain	0.4000
6:27824280:CG:C	acceptor_gain	0.3900
6:27824285:A:T	donor_gain	0.3900
6:27824306:T:TA	donor_gain	0.3900
6:27824308:T:TG	donor_gain	0.3900
6:27824432:GT:G	donor_gain	0.3700
6:27824433:TT:T	donor_gain	0.3700
6:27824298:GCTGA:G	donor_gain	0.3200
6:27824386:GTC:G	donor_gain	0.3200
6:27824387:TCT:T	donor_gain	0.3200
6:27824280:C:G	acceptor_gain	0.3100
6:27824364:G:GT	donor_gain	0.3100
6:27824370:C:A	donor_gain	0.3100

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000167315 (6:27822517 G>A,C), RS1000198241 (6:27822856 T>C), RS1000510851 (6:27823880 T>A), RS1002211115 (6:27824586 G>A,C), RS1005880844 (6:27824498 T>A,C,G), RS1007061623 (6:27824311 C>T), RS1009055384 (6:27824718 C>T), RS1009149219 (6:27823588 C>T), RS1009713672 (6:27823991 C>T), RS1009978044 (6:27824734 A>G), RS1010551108 (6:27823570 G>A,C), RS1010654156 (6:27823399 AT>A), RS1010972814 (6:27824604 A>T), RS1011789160 (6:27823977 G>A,C), RS1011916119 (6:27822453 T>C)

Disease associations

OMIM: gene MIM:602826 | disease phenotypes: MIM:619759

GenCC curated gene-disease

Disease	Classification	Inheritance
Tessadori-van Haaften neurodevelopmental syndrome 2	Moderate	Autosomal dominant

Mondo (1): Tessadori-van Haaften neurodevelopmental syndrome 2 (MONDO:0030730)

Orphanet (0):

HPO phenotypes

23 total (23 of 23 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000047	Hypospadias
HP:0000154	Wide mouth
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000565	Esotropia
HP:0000582	Upslanted palpebral fissure
HP:0000629	Periorbital fullness
HP:0000657	Oculomotor apraxia
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001344	Absent speech
HP:0001510	Growth delay
HP:0001763	Pes planus
HP:0002553	Highly arched eyebrow
HP:0002714	Downturned corners of mouth
HP:0003202	Skeletal muscle atrophy
HP:0003577	Congenital onset
HP:0004322	Short stature
HP:0005280	Depressed nasal bridge

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST004521_112	Autism spectrum disorder or schizophrenia	3.000000e-26
GCST004521_115	Autism spectrum disorder or schizophrenia	3.000000e-16
GCST004521_116	Autism spectrum disorder or schizophrenia	3.000000e-16
GCST004521_166	Autism spectrum disorder or schizophrenia	4.000000e-24
GCST004521_22	Autism spectrum disorder or schizophrenia	2.000000e-11
GCST004521_23	Autism spectrum disorder or schizophrenia	2.000000e-11
GCST004521_6	Autism spectrum disorder or schizophrenia	2.000000e-15
GCST004521_73	Autism spectrum disorder or schizophrenia	8.000000e-11
GCST008921_6	Asthma and major depressive disorder	1.000000e-09
GCST010002_50	Refractive error	4.000000e-34
GCST010142_16	Fish- and plant-related diet	2.000000e-10
GCST010142_19	Fish- and plant-related diet	4.000000e-10
GCST010142_34	Fish- and plant-related diet	7.000000e-09
GCST010142_35	Fish- and plant-related diet	8.000000e-09
GCST010142_42	Fish- and plant-related diet	1.000000e-08
GCST010142_7	Fish- and plant-related diet	3.000000e-12
GCST010702_75	Subcortical volume (MOSTest)	3.000000e-11
GCST010703_272	Brain morphology (MOSTest)	7.000000e-16

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008111	diet measurement
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5876 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 312 (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
CHEMBL3919831	AMREDOBRESIB	2	312

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

Binding affinities (BindingDB)

78 measured of 78 human assays (78 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
6-[1-[(5-fluoro-2-pyridinyl)methyl]-6-morpholin-4-ylimidazo[4,5-c]pyridin-2-yl]-3-methyl-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	1 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-[1-benzyl-2-[8-[[1-(2-methoxyethyl)piperidin-4-yl]amino]-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]benzimidazol-5-yl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one	IC50	3 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-morpholin-4-yl-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	3 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-morpholin-4-yl-1-(pyridin-2-ylmethyl)benzimidazol-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	3 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1-benzyl-5-methyl-4-phenylimidazol-2-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	4 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-morpholin-4-yl-1-(pyridin-3-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	4 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-[1-benzyl-2-[3-methyl-8-(methylamino)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]benzimidazol-5-yl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one	IC50	5 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[6-morpholin-4-yl-1-(pyridin-2-ylmethyl)benzimidazol-2-yl]-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	5 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-morpholin-4-yl-1-(pyridin-3-ylmethyl)benzimidazol-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	5 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1-benzylbenzimidazol-2-yl)-3-methyl-N-(1-methylpiperidin-4-yl)-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	7 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1-benzyl-6-morpholin-4-ylbenzimidazol-2-yl)-N-[1-(2-methoxyethyl)piperidin-4-yl]-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	7 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[6-(dimethylamino)-1-(pyridin-2-ylmethyl)benzimidazol-2-yl]-3-methyl-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	7 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1,5-dimethyl-4-phenoxypyrazol-3-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	8 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1-benzylbenzimidazol-2-yl)-N-[1-(2-methoxyethyl)piperidin-4-yl]-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	8 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-(4-methylpiperazin-1-yl)-1-(pyridin-2-ylmethyl)benzimidazol-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	8 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-(4-methylpiperazin-1-yl)-1-(pyridin-3-ylmethyl)benzimidazol-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	8 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[1-[(4-fluorophenyl)methyl]benzimidazol-2-yl]-N-[1-(2-methoxyethyl)piperidin-4-yl]-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	9 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[1-[(3,4-difluorophenyl)methyl]benzimidazol-2-yl]-N-[1-(2-methoxyethyl)piperidin-4-yl]-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	9 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[1-benzyl-6-(4-methylpiperazin-1-yl)imidazo[4,5-c]pyridin-2-yl]-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	9 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[9-benzyl-2-(4-methylpiperazin-1-yl)purin-8-yl]-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	9 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[1-benzyl-6-(4-methylpiperazin-1-yl)benzimidazol-2-yl]-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	9 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[6-[(3R)-3-methylmorpholin-4-yl]-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	9 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[6-[(3S)-3-methylmorpholin-4-yl]-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	9 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1-benzyl-6-morpholin-4-ylbenzimidazol-2-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	10 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[6-morpholin-4-yl-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	10 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[5-(oxan-4-yl)-1-(pyridin-2-ylmethyl)benzimidazol-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	11 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-(4-methylpiperazin-1-yl)-1-(pyridin-3-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	12 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-(4-methylpiperazin-1-yl)-1-(pyridin-4-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	12 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-methoxyacetamide	IC50	12.8 nM	US-9125915: Antitumor agent
N,3-dimethyl-6-[6-(4-methylpiperazin-1-yl)-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	13 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[6-(dimethylamino)-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-3-methyl-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	13 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[6-morpholin-4-yl-1-(pyridin-3-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-N-[(3R)-oxolan-3-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	13 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[1-benzyl-6-(4-methylpiperazin-1-yl)imidazo[4,5-c]pyridin-2-yl]-3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyrazine	IC50	14 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-N-propan-2-yl-6-[1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	14 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1-benzyl-4,5-dimethylimidazol-2-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	15 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[6-methyl-1-(pyridin-2-ylmethyl)benzimidazol-2-yl]-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	15 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[1-benzyl-6-(4-methylpiperazin-1-yl)imidazo[4,5-c]pyridin-2-yl]-N-ethyl-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	17 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[1-[(6-methyl-2-pyridinyl)methyl]-6-morpholin-4-ylimidazo[4,5-c]pyridin-2-yl]-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	17 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
2-[7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-methylacetamide	IC50	17.3 nM	US-9125915: Antitumor agent
6-(4-benzyl-1,5-dimethylpyrazol-3-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	18 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(3-benzylimidazo[4,5-b]pyridin-2-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	18 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-N-propan-2-yl-6-[6-propan-2-yl-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	18 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
methyl 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate	IC50	18.2 nM	US-9125915: Antitumor agent
3-methyl-6-[6-morpholin-4-yl-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-N-[(3R)-oxolan-3-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	20 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-N-propan-2-yl-6-[1-(pyridin-2-ylmethyl)benzimidazol-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	20 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
2-[7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-(2-hydroxyethyl)acetamide	IC50	21 nM	US-9125915: Antitumor agent
6-(1-benzylbenzimidazol-2-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	22 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[1-benzyl-6-(4-methylpiperazin-1-yl)imidazo[4,5-c]pyridin-2-yl]-3-methyl-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	26 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[6-methyl-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	28 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1-benzyl-4,5-dimethylimidazol-2-yl)-3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyrazine	IC50	31 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors

ChEMBL bioactivities

65 potent at pChembl≥5 of 66 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	CHEMBL3930178
8.52	IC50	3	nM	CHEMBL3938152
8.52	IC50	3	nM	CHEMBL3953268
8.52	IC50	3	nM	CHEMBL3916639
8.40	IC50	4	nM	CHEMBL3979803
8.40	IC50	4	nM	CHEMBL3959499
8.30	IC50	5	nM	CHEMBL3913643
8.30	IC50	5	nM	CHEMBL3939182
8.30	IC50	5	nM	CHEMBL3935504
8.15	IC50	7	nM	CHEMBL3983932
8.15	IC50	7	nM	CHEMBL3920322
8.15	IC50	7	nM	CHEMBL3923899
8.10	IC50	8	nM	CHEMBL3929450
8.10	IC50	8	nM	CHEMBL3923105
8.10	IC50	8	nM	CHEMBL3929086
8.10	IC50	8	nM	CHEMBL3927028
8.05	IC50	9	nM	CHEMBL3941148
8.05	IC50	9	nM	CHEMBL3970690
8.05	IC50	9	nM	CHEMBL3908717
8.05	IC50	9	nM	CHEMBL3951550
8.05	IC50	9	nM	AMREDOBRESIB
8.05	IC50	9	nM	CHEMBL4112988
8.05	IC50	9	nM	CHEMBL3893231
8.01	Kd	9.891	nM	CHEMBL5653589
8.01	ED50	9.891	nM	CHEMBL5653589
8.00	IC50	10	nM	CHEMBL3914807
8.00	IC50	10	nM	CHEMBL3902208
7.96	IC50	11	nM	CHEMBL3907651
7.92	IC50	12	nM	CHEMBL3973914
7.92	IC50	12	nM	CHEMBL3966649
7.89	IC50	13	nM	CHEMBL3928047
7.89	IC50	13	nM	CHEMBL3951605
7.89	IC50	13	nM	CHEMBL4114198
7.85	IC50	14	nM	CHEMBL3919702
7.85	IC50	14	nM	CHEMBL3946335
7.82	IC50	15	nM	CHEMBL3916156
7.82	IC50	15	nM	CHEMBL3937464
7.77	IC50	17	nM	CHEMBL3956797
7.77	IC50	17	nM	CHEMBL3914869
7.75	IC50	18	nM	CHEMBL3891629
7.75	IC50	18	nM	CHEMBL3947502
7.75	IC50	18	nM	CHEMBL3956941
7.70	IC50	20	nM	CHEMBL4115491
7.70	IC50	20	nM	CHEMBL3960315
7.66	IC50	22	nM	CHEMBL3946480
7.58	IC50	26	nM	CHEMBL3929241
7.55	IC50	28	nM	CHEMBL3909523
7.51	IC50	31	nM	CHEMBL3985926
7.51	IC50	31	nM	CHEMBL4107079
7.50	IC50	32	nM	CHEMBL3916033

PubChem BioAssay actives

2 with measured affinity, of 108 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148510: Binding affinity to human HIST1H4A incubated for 45 mins by Kinobead based pull down assay	kd	0.0099	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148510: Binding affinity to human HIST1H4A incubated for 45 mins by Kinobead based pull down assay	kd	4.0927	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression	2
Acetaminophen	increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	affects cotreatment, decreases expression	1
methylmercuric chloride	decreases expression	1
methylselenic acid	decreases expression	1
potassium perchlorate	decreases expression	1
decabromobiphenyl ether	affects expression	1
2-methyl-4-isothiazolin-3-one	decreases expression	1
perfluorooctanoic acid	affects cotreatment, decreases expression	1
perfluorooctane sulfonic 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, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
perfluorobutanesulfonic acid	decreases expression, affects cotreatment	1
bisphenol S	affects cotreatment, increases expression	1
bis-N,N-dimethylamino-2-(N-methylpyrrolyl)methyl cyclopentadienyl titanium (IV)	decreases expression	1
(+)-JQ1 compound	increases expression	1
Arsenic Trioxide	decreases expression	1
Air Pollutants	increases abundance, decreases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	decreases methylation	1
Curcumin	increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Dimethyl Sulfoxide	increases expression	1
Doxorubicin	increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Indomethacin	affects cotreatment, increases expression	1
Lucanthone	decreases expression	1

ChEMBL screening assays

14 unique, capped per target: 14 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2175621	Binding	Binding affinity to fluorescein-labeled Histone H4(1-20) by spectrofluorometry	Pharmacophore-based virtual screening and biological evaluation of small molecule inhibitors for protein arginine methylation. — J Med Chem

Clinical trials (associated diseases)

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