EZH1

Summary

EZH1 (enhancer of zeste 1 polycomb repressive complex 2 subunit, HGNC:3526) is a protein-coding gene on chromosome 17q21.2, encoding Histone-lysine N-methyltransferase EZH1 (Q92800). Polycomb group (PcG) protein.

EZH1 is a component of a noncanonical Polycomb repressive complex-2 (PRC2) that mediates methylation of histone H3 (see MIM 602812) lys27 (H3K27) and functions in the maintenance of embryonic stem cell pluripotency and plasticity (Shen et al., 2008 [PubMed 19026780]).

Source: NCBI Gene 2145 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Strong, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 100 total — 5 likely-pathogenic
• Druggable target: yes — 5 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001991

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3526
Approved symbol	EZH1
Name	enhancer of zeste 1 polycomb repressive complex 2 subunit
Location	17q21.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0388, KMT6B
Ensembl gene	ENSG00000108799
Ensembl biotype	protein_coding
OMIM	601674
Entrez	2145

Gene structure

Transcript identifiers

Ensembl transcripts: 34 — 19 protein_coding, 9 retained_intron, 4 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000415827, ENST00000428826, ENST00000585455, ENST00000585550, ENST00000585893, ENST00000585912, ENST00000586089, ENST00000586103, ENST00000586382, ENST00000586714, ENST00000586867, ENST00000586935, ENST00000587179, ENST00000588239, ENST00000588897, ENST00000589846, ENST00000590078, ENST00000590082, ENST00000590783, ENST00000591330, ENST00000592492, ENST00000592743, ENST00000593148, ENST00000593214, ENST00000909306, ENST00000909307, ENST00000909308, ENST00000909309, ENST00000909310, ENST00000909311, ENST00000939633, ENST00000939634, ENST00000966141, ENST00000966142

RefSeq mRNA: 4 — MANE Select: NM_001991 NM_001321079, NM_001321081, NM_001321082, NM_001991

CCDS: CCDS32659, CCDS82129, CCDS82130

Canonical transcript exons

ENST00000428826 — 21 exons

Exon	Start	End
ENSE00001348045	42730828	42730918
ENSE00002821591	42745011	42745040
ENSE00002918356	42700275	42702592
ENSE00003458583	42705088	42705183
ENSE00003458641	42707958	42708083
ENSE00003458786	42728825	42728952
ENSE00003473976	42720273	42720449
ENSE00003481085	42704602	42704683
ENSE00003514136	42706007	42706185
ENSE00003526553	42713209	42713389
ENSE00003539171	42712289	42712485
ENSE00003549826	42718454	42718617
ENSE00003562465	42727635	42727763
ENSE00003566018	42717976	42718067
ENSE00003581836	42702877	42702961
ENSE00003600173	42719105	42719207
ENSE00003607369	42722795	42722915
ENSE00003641689	42708876	42708916
ENSE00003666993	42703740	42703820
ENSE00003678145	42709846	42709937
ENSE00003686516	42724305	42724424

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 97.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.3297 / max 203.9290, expressed in 1731 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
166184	9.3297	1731

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar hemisphere	UBERON:0002245	97.89	gold quality
cerebellar cortex	UBERON:0002129	97.85	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.78	gold quality
cerebellum	UBERON:0002037	97.32	gold quality
tibial nerve	UBERON:0001323	96.63	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	96.48	gold quality
calcaneal tendon	UBERON:0003701	96.43	gold quality
left ovary	UBERON:0002119	96.24	gold quality
sural nerve	UBERON:0015488	96.05	gold quality
olfactory bulb	UBERON:0002264	95.90	gold quality
right ovary	UBERON:0002118	95.69	gold quality
endocervix	UBERON:0000458	95.63	gold quality
inferior olivary complex	UBERON:0002127	95.61	gold quality
mucosa of stomach	UBERON:0001199	95.50	gold quality
body of uterus	UBERON:0009853	95.27	gold quality
subcutaneous adipose tissue	UBERON:0002190	95.08	gold quality
gluteal muscle	UBERON:0002000	94.94	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	94.88	gold quality
right uterine tube	UBERON:0001302	94.85	gold quality
apex of heart	UBERON:0002098	94.72	gold quality
right frontal lobe	UBERON:0002810	94.69	gold quality
ectocervix	UBERON:0012249	94.67	gold quality
tendon	UBERON:0000043	94.65	gold quality
popliteal artery	UBERON:0002250	94.53	gold quality
tibial artery	UBERON:0007610	94.53	gold quality
cerebellar vermis	UBERON:0004720	94.49	gold quality
right lung	UBERON:0002167	94.42	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.37	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.34	gold quality
lower esophagus	UBERON:0013473	94.33	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

120 targeting EZH1, 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-4481	100.00	66.42	1669
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-6783-3P	99.89	67.92	2059

Literature-anchored findings (GeneRIF, showing 23)

• EZH1 maintains repressive chromatin through different mechanisms. (PMID:19026781)
• The related enzymatic subunits EZH1 and EZH2 undergo an expression switch during blood cell development. (PMID:25578878)
• EZH1, SUZ12 and UXT work synergistically to regulate pathway activation in the nucleus. (PMID:27127229)
• These evidences suggest that EZH2 and EZH1 are important in the counter-balancing mechanisms controlling proliferation/resting of lymphoid cells. The disruption of the balanced EZH2/EZH1 ratio may play important roles in the pathogenesis of lymphomas (PMID:27311868)
• a hot-spot mutation in EZH1 is the second most frequent genetic alteration in autonomous thyroid adenomas; the association between EZH1 and TSHR mutations suggests a 2-hit model for the pathogenesis of these tumors, whereby constitutive activation of the cAMP pathway and EZH1 mutations cooperate to induce the hyperproliferation of thyroid cells (PMID:27500488)
• Expression of the EZH2 homolog EZH1 is reduced in EZH2-deficient CML LICs, creating a scenario resembling complete loss of PRC2. EZH2 dependence of CML LICs raises prospects for improved therapy of TKI-resistant CML and/or eradication of disease by addition of EZH2 inhibitors (PMID:27630126)
• The authors report a novel PRC2-Ezh1 function that utilizes Ezh1beta as an adaptive stress sensor in the cytoplasm, thus allowing postmitotic cells to maintain tissue integrity in response to environmental changes. (PMID:28346433)
• pVHL loss causes the transcriptional activation of hypoxia-inducible factor (HIF) target genes, including many genes that encode histone lysine demethylases. (PMID:28701475)
• Data show that embryonic stem cells with deletion of EZH1 or EZH2 fail to differentiate into ectoderm lineages. (PMID:28939884)
• identification of EZH1 as a repressor of haematopoietic multipotency in the early mammalian embryo (PMID:29342143)
• EZH1 mutations predominantly occurred in clinically benign follicular neoplasms without RAS mutations. (PMID:29723601)
• Overexpression the EZH1 gene inhibited HK-2 cell apoptosis, reduced ROS levels, and down-regulated the expressions of IL-1beta, IL-6, TNF-alpha, Bax and Cyt C mRNA and protein, and increased the expressions of Bcl-2 and NFKBIA, CXCL8 and cyclin D1, indicating that overexpression of EZH1 suppressed NF-kappaB signaling in aristolochic acid-injured HK-2 cells. (PMID:30688289)
• functions mostly within canonical PRC2 and exhibits proliferation-dependent redundancy that shapes mutational signatures in cancer (PMID:30867289)
• Findings highlight the role of EZH1 in non-histone lysine methylation, indicating that cooperation between AML1-ETO and EZH1 and AML1-ETO site-specific lysine methylation promote AML1-ETO transcriptional repression in leukemia. (PMID:31699991)
• Targeting Excessive EZH1 and EZH2 Activities for Abnormal Histone Methylation and Transcription Network in Malignant Lymphomas. (PMID:31747604)
• Structures of monomeric and dimeric PRC2:EZH1 reveal flexible modules involved in chromatin compaction. (PMID:33514705)
• TRIM21 improves apatinib treatment in gastric cancer through suppressing EZH1 stability. (PMID:34856418)
• Downregulation of the enhancer of zeste homolog 1 transcriptional factor predicts poor prognosis of triple-negative breast cancer patients. (PMID:35846880)
• Polycomb EZH1 regulates cell cycle/5-fluorouracil sensitivity of neuroblastoma cells in concert with MYCN. (PMID:36052716)
• The role of EZH1 and EZH2 in development and cancer. (PMID:36476271)
• Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders. (PMID:37433783)
• The competitive mechanism of EZH1 and EZH2 in promoting oral squamous cell carcinoma. (PMID:38309675)
• Clinical Significance of Upregulation of EZH1 Expression in Hepatocellular Carcinoma Tissues. (PMID:38554427)

Cross-species orthologs

21 orthologs

Organism	Symbol	Gene ID
danio_rerio	ezh1	ENSDARG00000037894
mus_musculus	Ezh1	ENSMUSG00000006920
rattus_norvegicus	Ezh1	ENSRNOG00000020336
drosophila_melanogaster	ash1	FBGN0005386
drosophila_melanogaster	trr	FBGN0023518
drosophila_melanogaster	Set2	FBGN0030486
drosophila_melanogaster	CG4565	FBGN0037841
drosophila_melanogaster	G9a	FBGN0040372
drosophila_melanogaster	egg	FBGN0086908
caenorhabditis_elegans	set-32	WBGENE00008062
caenorhabditis_elegans		WBGENE00008206
caenorhabditis_elegans		WBGENE00008527
caenorhabditis_elegans		WBGENE00011729
caenorhabditis_elegans	met-1	WBGENE00016603
caenorhabditis_elegans		WBGENE00018023
caenorhabditis_elegans		WBGENE00019584
caenorhabditis_elegans		WBGENE00019690
caenorhabditis_elegans		WBGENE00019883
caenorhabditis_elegans		WBGENE00020006
caenorhabditis_elegans		WBGENE00020919
caenorhabditis_elegans		WBGENE00021282

Paralogs (19): KMT2C (ENSG00000055609), SETD1A (ENSG00000099381), SUV39H1 (ENSG00000101945), EZH2 (ENSG00000106462), NSD2 (ENSG00000109685), ASH1L (ENSG00000116539), KMT2A (ENSG00000118058), SETDB2 (ENSG00000136169), SETD1B (ENSG00000139718), SETDB1 (ENSG00000143379), NSD3 (ENSG00000147548), SETBP1 (ENSG00000152217), SUV39H2 (ENSG00000152455), NSD1 (ENSG00000165671), KMT2D (ENSG00000167548), EHMT1 (ENSG00000181090), SETD2 (ENSG00000181555), EHMT2 (ENSG00000204371), KMT2B (ENSG00000272333)

Protein

Protein identifiers

Histone-lysine N-methyltransferase EZH1 — Q92800 (reviewed: Q92800)

Alternative names: ENX-2, Enhancer of zeste homolog 1

All UniProt accessions (10): Q92800, A0A0A0MSY9, K7EIH5, K7EJU6, K7EK26, K7EK66, K7EM79, K7ENP2, K7EPC0, K7ESB9

UniProt curated annotations — full annotation on UniProt →

Function. Polycomb group (PcG) protein. Catalytic subunit of the PRC2/EED-EZH1 complex, which methylates ‘Lys-27’ of histone H3, leading to transcriptional repression of the affected target gene. Able to mono-, di- and trimethylate ‘Lys-27’ of histone H3 to form H3K27me1, H3K27me2 and H3K27me3, respectively. Required for embryonic stem cell derivation and self-renewal, suggesting that it is involved in safeguarding embryonic stem cell identity. Compared to EZH2-containing complexes, it is less abundant in embryonic stem cells, has weak methyltransferase activity and plays a less critical role in forming H3K27me3, which is required for embryonic stem cell identity and proper differentiation.

Subunit / interactions. Component of the PRC2/EED-EZH1 complex, which includes EED, EZH1, SUZ12, RBBP4 and AEBP2. The PRC2/EED-EZH1 is less abundant than the PRC2/EED-EZH2 complex, has weak methyltransferase activity and compacts chromatin in the absence of the methyltransferase cofactor S-adenosyl-L-methionine (SAM). Interacts with EZHIP; the interaction blocks EZH1 methyltransferase activity.

Subcellular location. Nucleus.

Similarity. Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. EZ subfamily.

Isoforms (5)

UniProt ID	Names	Canonical?
Q92800-1	1	yes
Q92800-2	2
Q92800-3	3
Q92800-4	4
Q92800-5	5

RefSeq proteins (4): NP_001308008, NP_001308010, NP_001308011, NP_001982* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001005	SANT/Myb	Domain
IPR001214	SET_dom	Domain
IPR021654	EZH1/EZH2_N	Domain
IPR026489	CXC_dom	Domain
IPR033467	Tesmin/TSO1-like_CXC	Domain
IPR041343	PRC2_HTH_1	Domain
IPR041355	Pre-SET_CXC	Domain
IPR044438	EZH1_SET	Domain
IPR045318	EZH1/2-like	Family
IPR046341	SET_dom_sf	Homologous_superfamily
IPR048358	EZH1/2_MCSS	Domain

Pfam: PF00856, PF11616, PF18118, PF18264, PF21358

Catalyzed reactions (Rhea), 1 shown:

• L-lysyl(27)-[histone H3] + 3 S-adenosyl-L-methionine = N(6),N(6),N(6)-trimethyl-L-lysyl(27)-[histone H3] + 3 S-adenosyl-L-homocysteine + 3 H(+) (RHEA:60292)

UniProt features (56 total): helix 15, strand 13, sequence conflict 9, splice variant 4, turn 4, compositionally biased region 3, domain 2, region of interest 2, chain 1, mutagenesis site 1, short sequence motif 1, cross-link 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
7TD5	X-RAY DIFFRACTION	2.99
7KSO	ELECTRON MICROSCOPY	3.9
7KSR	ELECTRON MICROSCOPY	4.1
7KTP	ELECTRON MICROSCOPY	4.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92800-F1	75.05	0.39

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 (1): 327

Mutagenesis-validated functional residues (1):

Position	Phenotype
690	loss of methyltransferase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-212300	PRC2 methylates histones and DNA

MSigDB gene sets: 257 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, FREAC2_01, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, FOXO4_01, FOXO1_01, BOYLAN_MULTIPLE_MYELOMA_D_DN, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, GOBP_HIPPOCAMPUS_DEVELOPMENT, GOBP_PALLIUM_DEVELOPMENT, HFH1_01, GOBP_HEAD_DEVELOPMENT, GOBP_CHROMATIN_REMODELING, GOBP_HETEROCHROMATIN_ORGANIZATION

GO Biological Process (9): negative regulation of transcription by RNA polymerase II (GO:0000122), chromatin remodeling (GO:0006338), anatomical structure morphogenesis (GO:0009653), hippocampus development (GO:0021766), heterochromatin formation (GO:0031507), subtelomeric heterochromatin formation (GO:0031509), methylation (GO:0032259), positive regulation of transcription by RNA polymerase II (GO:0045944), chromatin organization (GO:0006325)

GO Molecular Function (12): chromatin binding (GO:0003682), transcription corepressor activity (GO:0003714), protein-lysine N-methyltransferase activity (GO:0016279), nucleosome binding (GO:0031491), histone H3K27 methyltransferase activity (GO:0046976), molecular condensate scaffold activity (GO:0140693), histone H3K27 trimethyltransferase activity (GO:0140951), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740), histone methyltransferase activity (GO:0042054), histone binding (GO:0042393)

GO Cellular Component (5): chromosome, telomeric region (GO:0000781), heterochromatin (GO:0000792), nucleus (GO:0005634), nucleoplasm (GO:0005654), ESC/E(Z) complex (GO:0035098)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Epigenetic regulation of gene expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
negative regulation of DNA-templated transcription	2
anatomical structure development	2
binding	2
protein methyltransferase activity	2
chromatin organization	1
developmental process	1
pallium development	1
limbic system development	1
cellular component assembly	1
heterochromatin boundary formation	1
negative regulation of gene expression, epigenetic	1
heterochromatin organization	1
chromosome, telomeric region	1
constitutive heterochromatin formation	1
metabolic process	1
positive regulation of DNA-templated transcription	1
cellular component organization	1
transcription coregulator activity	1
lysine N-methyltransferase activity	1
chromatin binding	1
protein-containing complex binding	1
protein-lysine N-methyltransferase activity	1
histone H3 methyltransferase activity	1
protein-macromolecule adaptor activity	1
histone H3K27 methyltransferase activity	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
histone modifying activity	1
protein binding	1
chromosomal region	1
chromatin	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
PcG protein complex	1
histone methyltransferase complex	1

Protein interactions and networks

STRING

2564 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EZH1	SUZ12	Q15022	997
EZH1	EED	O75530	997
EZH1	RBBP4	P31149	995
EZH1	RBBP7	Q16576	994
EZH1	EZH2	Q15910	981
EZH1	JARID2	Q92833	959
EZH1	AEBP2	Q6ZN18	893
EZH1	RING1	Q06587	783
EZH1	MTF2	Q9Y483	758
EZH1	PHF19	Q5T6S3	758
EZH1	RNF2	Q99496	738
EZH1	EPOP	A6NHQ4	708
EZH1	KDM6A	O15550	706
EZH1	PHF1	O43189	704
EZH1	BMI1	P35226	695

IntAct

175 interactions, top by confidence:

A	B	Type	Score
SUZ12	EED	psi-mi:“MI:0914”(association)	0.910
EZH2	PHF1	psi-mi:“MI:0914”(association)	0.900
PHF1	EED	psi-mi:“MI:0914”(association)	0.790
RBBP4	CDK2AP1	psi-mi:“MI:0914”(association)	0.790
EZH1	EED	psi-mi:“MI:0915”(physical association)	0.740
PHF19	EED	psi-mi:“MI:0914”(association)	0.730
RBBP7	HAT1	psi-mi:“MI:0914”(association)	0.730
AEBP2	EED	psi-mi:“MI:0914”(association)	0.650
MTF2	EED	psi-mi:“MI:0914”(association)	0.640
SUZ12	EPOP	psi-mi:“MI:0914”(association)	0.640
LCOR	PHF1	psi-mi:“MI:0914”(association)	0.640
JARID2	EED	psi-mi:“MI:0914”(association)	0.640
EZH1	TJP2	psi-mi:“MI:0407”(direct interaction)	0.590
RBBP4	TNRC18	psi-mi:“MI:0914”(association)	0.530
RBBP7	EPOP	psi-mi:“MI:0914”(association)	0.530
PHF19	EPOP	psi-mi:“MI:0914”(association)	0.530
PHF1	EPOP	psi-mi:“MI:0914”(association)	0.530
EZH1	EPOP	psi-mi:“MI:0914”(association)	0.530
EED	EPOP	psi-mi:“MI:0914”(association)	0.530

BioGRID (147): EZH1 (Affinity Capture-MS), EZH1 (Affinity Capture-MS), EZH1 (Affinity Capture-Western), EZH1 (Affinity Capture-MS), EZH1 (Affinity Capture-MS), EED (Two-hybrid), EZH1 (Affinity Capture-MS), EZH1 (Affinity Capture-MS), EZH1 (Affinity Capture-Western), EZH1 (Affinity Capture-MS), EZH1 (Affinity Capture-MS), EZH1 (Affinity Capture-MS), EZH1 (Affinity Capture-MS), AEBP2 (Affinity Capture-MS), BLVRA (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2JZ79, A1ZA92, A6QQR4, A7E2Z2, A8JQ65, A8WRG3, B3NYS4, B4K6T8, B4R0A5, B6VQ60, F4JZ68, O75164, O94640, P06700, P33294, P42124, P50526, P70351, Q04688, Q08BS4, Q14149, Q15910, Q21921, Q28D84, Q28Z18, Q2NKX8, Q4R381, Q4V863, Q5RD88, Q5RDS6, Q5RDX4, Q60L58, Q61188, Q61IS6, Q640I9, Q6DTM3, Q6PL18, Q757M7, Q8CDM1, Q8K3E5

Diamond homologs: A0A1L7TZE5, A4IGY9, A7E2Z2, A8XI75, J9VWH9, O43463, O54864, O60016, O65312, O82175, O88491, O88974, O96028, P20659, P42124, P45975, P46995, P55200, P70351, P93831, Q03164, Q06ZW3, Q08BR4, Q08BS4, Q0VD24, Q15047, Q15910, Q24742, Q28CQ7, Q28D84, Q294B9, Q2NL30, Q32PH7, Q4PB36, Q4R381, Q4R3E0, Q4V863, Q53H47, Q5DW34, Q5F3W5

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 103 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ras activation upon Ca2+ influx through NMDA receptor	5	38.1×	1e-05
Unblocking of NMDA receptors, glutamate binding and activation	5	36.2×	1e-05
Negative regulation of NMDA receptor-mediated neuronal transmission	5	36.2×	1e-05
Long-term potentiation	5	31.7×	3e-05
Assembly and cell surface presentation of NMDA receptors	8	27.1×	7e-08
Neurexins and neuroligins	9	23.6×	3e-08
PRC2 methylates histones and DNA	11	22.3×	8e-10
Transcriptional Regulation by E2F6	5	19.5×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	9	52.8×	5e-11
protein localization to synapse	6	46.4×	6e-07
receptor clustering	7	44.1×	7e-08
regulation of postsynaptic membrane neurotransmitter receptor levels	7	35.0×	3e-07
stem cell differentiation	5	15.2×	1e-03
epidermal growth factor receptor signaling pathway	5	12.5×	3e-03
cell-cell adhesion	11	11.3×	7e-07
negative regulation of transforming growth factor beta receptor signaling pathway	6	10.5×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	5
Uncertain significance	66
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
2570596	NM_001991.5(EZH1):c.2191C>G (p.Gln731Glu)	Likely pathogenic
2570598	NM_001991.5(EZH1):c.1453G>T (p.Glu485Ter)	Likely pathogenic
2570599	NM_001991.5(EZH1):c.932-1G>A	Likely pathogenic
2570600	NM_001991.5:c.(664+1_665-1)_(1401+1_1402-1)del	Likely pathogenic
4538614	NM_001991.5(EZH1):c.1660+1G>A	Likely pathogenic

SpliceAI

2809 predictions. Top by Δscore:

Variant	Effect	Δscore
17:42702871:CCTCA:C	donor_loss	1.0000
17:42702872:CTCAC:C	donor_loss	1.0000
17:42702873:TCA:T	donor_loss	1.0000
17:42702876:C:G	donor_loss	1.0000
17:42702959:CCA:C	acceptor_gain	1.0000
17:42702960:CA:C	acceptor_gain	1.0000
17:42702960:CAC:C	acceptor_gain	1.0000
17:42702962:C:CC	acceptor_gain	1.0000
17:42703048:CCCAG:C	acceptor_gain	1.0000
17:42703049:CCAG:C	acceptor_gain	1.0000
17:42703050:C:T	acceptor_gain	1.0000
17:42703051:A:T	acceptor_gain	1.0000
17:42703735:CTCA:C	donor_loss	1.0000
17:42703736:TCA:T	donor_loss	1.0000
17:42703737:CACC:C	donor_loss	1.0000
17:42703738:A:AC	donor_gain	1.0000
17:42703738:A:AG	donor_loss	1.0000
17:42703738:AC:A	donor_gain	1.0000
17:42703739:C:CC	donor_gain	1.0000
17:42703739:CC:C	donor_gain	1.0000
17:42703739:CCT:C	donor_gain	1.0000
17:42703816:AAAAT:A	acceptor_gain	1.0000
17:42703817:AAAT:A	acceptor_gain	1.0000
17:42703818:AAT:A	acceptor_gain	1.0000
17:42703819:AT:A	acceptor_gain	1.0000
17:42703819:ATC:A	acceptor_loss	1.0000
17:42703820:TC:T	acceptor_loss	1.0000
17:42703821:C:CC	acceptor_gain	1.0000
17:42703821:CTGT:C	acceptor_loss	1.0000
17:42703823:G:C	acceptor_gain	1.0000

AlphaMissense

4993 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:42702572:A:G	L735P	1.000
17:42702575:G:T	A734D	1.000
17:42702591:A:G	Y729H	1.000
17:42702877:C:A	R728M	1.000
17:42702880:T:C	Y727C	1.000
17:42702881:A:C	Y727D	1.000
17:42702881:A:G	Y727H	1.000
17:42702883:T:A	D726V	1.000
17:42702883:T:C	D726G	1.000
17:42702883:T:G	D726A	1.000
17:42702884:C:G	D726H	1.000
17:42702885:A:C	F725L	1.000
17:42702885:A:T	F725L	1.000
17:42702886:A:C	F725C	1.000
17:42702886:A:G	F725S	1.000
17:42702887:A:G	F725L	1.000
17:42702889:A:G	F724S	1.000
17:42702892:A:C	L723R	1.000
17:42702892:A:G	L723P	1.000
17:42702892:A:T	L723H	1.000
17:42702896:C:T	E722K	1.000
17:42702910:A:T	I717N	1.000
17:42702922:G:T	A713D	1.000
17:42702924:A:C	F712L	1.000
17:42702924:A:T	F712L	1.000
17:42702925:A:G	F712S	1.000
17:42702926:A:G	F712L	1.000
17:42702928:A:C	I711S	1.000
17:42702928:A:G	I711T	1.000
17:42702928:A:T	I711N	1.000

dbSNP variants (sampled 300 via entrez): RS1000004745 (17:42714622 C>A,T), RS1000004780 (17:42718139 T>A,C,G), RS1000010689 (17:42737624 CAAACT>C), RS1000128806 (17:42703017 A>G,T), RS1000215170 (17:42717538 T>C), RS1000322448 (17:42724346 G>A), RS1000381232 (17:42724004 T>C), RS1000516020 (17:42711742 C>A,T), RS1000521493 (17:42744441 TGAG>T), RS1000569823 (17:42712093 C>T), RS1000607089 (17:42720033 A>G), RS1000671993 (17:42717072 G>A), RS1000730917 (17:42704857 C>T), RS1000871843 (17:42730152 CTTG>C), RS1000932061 (17:42733490 A>C)

Disease associations

OMIM: gene MIM:601674 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Strong	Autosomal dominant

Mondo (1): neurodevelopmental disorder (MONDO:0700092)

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST008839_506	Height	4.000000e-12
GCST90000025_586	Appendicular lean mass	2.000000e-12
GCST90020024_519	A body shape index	4.000000e-10
GCST90020027_416	Waist-hip index	2.000000e-13

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004980	appendicular lean mass
EFO:0007789	BMI-adjusted waist circumference
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL2189116 (SINGLE PROTEIN), CHEMBL3137287 (PROTEIN COMPLEX), CHEMBL6193805 (PROTEIN-PROTEIN INTERACTION), CHEMBL6195582 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

5 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 4,773 (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
CHEMBL3414621	TAZEMETOSTAT	4	1,869
CHEMBL4080228	MEVROMETOSTAT	2	443
CHEMBL4597193	VALEMETOSTAT	2	193
CHEMBL3287735	GSK2816126	1	1,396
CHEMBL4297463	CPI-1205	1	872

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — 2.1.1.43 Histone methyltransferases (HMTs)

Most potent curated ligand interactions (4 total), top 4:

Ligand	Action	Affinity	Parameter
tulmimetostat	Inhibition	10.22	pIC50
valemetostat	Inhibition	7.8	pIC50
zeprumetostat	Inhibition	7.72	pIC50
GSK343	Inhibition	6.62	pIC50

ChEMBL bioactivities

111 potent at pChembl≥5 of 112 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.00	IC50	0.1	nM	CHEMBL4159112
9.40	IC50	0.4	nM	CHEMBL4161265
9.36	IC50	0.44	nM	VALEMETOSTAT
9.33	IC50	0.47	nM	CHEMBL5197386
9.30	IC50	0.5	nM	CHEMBL4165937
9.22	IC50	0.6	nM	CHEMBL4160111
9.10	IC50	0.8	nM	CHEMBL4172576
8.57	IC50	2.7	nM	CHEMBL4164687
8.54	IC50	2.9	nM	CHEMBL4170327
8.48	IC50	3.3	nM	CHEMBL4162316
8.42	IC50	3.8	nM	CHEMBL4177454
8.40	IC50	4	nM	CHEMBL4162499
8.40	IC50	4	nM	CHEMBL4170753
8.40	IC50	4	nM	CHEMBL4174176
8.40	IC50	4	nM	TAZEMETOSTAT
8.39	IC50	4.1	nM	CHEMBL4169191
8.34	IC50	4.6	nM	CHEMBL4169368
8.34	IC50	4.6	nM	CHEMBL4162406
8.23	IC50	5.9	nM	CHEMBL4169598
8.22	IC50	6	nM	CHEMBL4167587
8.21	IC50	6.1	nM	CHEMBL4169762
8.19	IC50	6.5	nM	CHEMBL4176373
8.19	IC50	6.4	nM	CHEMBL4161444
8.15	IC50	7	nM	CHEMBL5185991
8.11	IC50	7.8	nM	CHEMBL4176554
8.08	IC50	8.4	nM	VALEMETOSTAT
8.08	IC50	8.31	nM	CHEMBL6032817
8.07	IC50	8.6	nM	CHEMBL5289464
7.92	IC50	12	nM	CHEMBL5840996
7.92	IC50	12	nM	CHEMBL5922751
7.89	IC50	13	nM	CHEMBL3414574
7.85	IC50	14	nM	CHEMBL5791232
7.82	IC50	15	nM	CHEMBL6011932
7.82	IC50	15	nM	CHEMBL5956024
7.77	IC50	17	nM	CHEMBL5954404
7.75	IC50	18	nM	CHEMBL5960885
7.70	IC50	20	nM	CHEMBL3770000
7.70	IC50	20	nM	CHEMBL6012111
7.68	IC50	21	nM	CHEMBL5187396
7.66	IC50	22	nM	CHEMBL5882348
7.66	IC50	22	nM	CHEMBL5982156
7.64	IC50	23	nM	CHEMBL5193486
7.64	IC50	23	nM	VALEMETOSTAT
7.50	IC50	32	nM	CHEMBL6022634
7.50	IC50	31.5	nM	VALEMETOSTAT
7.35	IC50	45	nM	CHEMBL3360855
7.35	IC50	45	nM	CHEMBL5196227
7.35	IC50	45	nM	CHEMBL3414619
7.35	Ki	45	nM	CHEMBL3672841
7.28	IC50	52	nM	CPI-1205

PubChem BioAssay actives

93 with measured affinity, of 174 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
5-ethyl-6-[ethyl(oxan-4-yl)amino]-N-[(4-methoxy-6-methyl-2-oxo-1H-pyridin-3-yl)methyl]-2-[(4-methylpiperazin-1-yl)methyl]-1-benzofuran-4-carboxamide	1350244: Inhibition of human N-terminal His-tagged EZH2/flag-tagged EED/SUZ12/AEBP2/RBAP48 A677G mutant (2 to end residues) expressed in baculovirus infected Sf9 insect cells using histone H3 (1 to 50 residues)-GGK as substrate after 2 hrs in presence of SAM by fluorescence assay	ic50	0.0001	uM
(2R)-7-chloro-2-[4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide	1868645: Inhibition of EZH1 (unknown origin)	ic50	0.0004	uM
2-chloro-6-[ethyl(oxan-4-yl)amino]-N-[(4-methoxy-6-methyl-2-oxo-1H-pyridin-3-yl)methyl]-5-methyl-1-benzofuran-4-carboxamide	1350244: Inhibition of human N-terminal His-tagged EZH2/flag-tagged EED/SUZ12/AEBP2/RBAP48 A677G mutant (2 to end residues) expressed in baculovirus infected Sf9 insect cells using histone H3 (1 to 50 residues)-GGK as substrate after 2 hrs in presence of SAM by fluorescence assay	ic50	0.0004	uM
(2R)-7-bromo-2-[4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide	1868645: Inhibition of EZH1 (unknown origin)	ic50	0.0005	uM
2-cyclopropyl-6-[ethyl(oxan-4-yl)amino]-N-[(4-methoxy-6-methyl-2-oxo-1H-pyridin-3-yl)methyl]-5-methyl-1-benzofuran-4-carboxamide	1350244: Inhibition of human N-terminal His-tagged EZH2/flag-tagged EED/SUZ12/AEBP2/RBAP48 A677G mutant (2 to end residues) expressed in baculovirus infected Sf9 insect cells using histone H3 (1 to 50 residues)-GGK as substrate after 2 hrs in presence of SAM by fluorescence assay	ic50	0.0005	uM
N-[(4-ethyl-6-methyl-2-oxo-1H-pyridin-3-yl)methyl]-6-[ethyl(oxan-4-yl)amino]-5-methyl-1-benzofuran-4-carboxamide	1350244: Inhibition of human N-terminal His-tagged EZH2/flag-tagged EED/SUZ12/AEBP2/RBAP48 A677G mutant (2 to end residues) expressed in baculovirus infected Sf9 insect cells using histone H3 (1 to 50 residues)-GGK as substrate after 2 hrs in presence of SAM by fluorescence assay	ic50	0.0006	uM
2-cyano-6-[ethyl(oxan-4-yl)amino]-N-[(4-methoxy-6-methyl-2-oxo-1H-pyridin-3-yl)methyl]-5-methyl-1-benzofuran-4-carboxamide	1350244: Inhibition of human N-terminal His-tagged EZH2/flag-tagged EED/SUZ12/AEBP2/RBAP48 A677G mutant (2 to end residues) expressed in baculovirus infected Sf9 insect cells using histone H3 (1 to 50 residues)-GGK as substrate after 2 hrs in presence of SAM by fluorescence assay	ic50	0.0008	uM
6-[ethyl(oxan-4-yl)amino]-N-[(4-methoxy-6-methyl-2-oxo-1H-pyridin-3-yl)methyl]-5-methyl-2-(trifluoromethyl)-1-benzofuran-4-carboxamide	1350244: Inhibition of human N-terminal His-tagged EZH2/flag-tagged EED/SUZ12/AEBP2/RBAP48 A677G mutant (2 to end residues) expressed in baculovirus infected Sf9 insect cells using histone H3 (1 to 50 residues)-GGK as substrate after 2 hrs in presence of SAM by fluorescence assay	ic50	0.0027	uM
6-[ethyl(oxan-4-yl)amino]-N-[(4-methoxy-6-methyl-2-oxo-1H-pyridin-3-yl)methyl]-2,5-dimethyl-1-benzofuran-4-carboxamide	1350244: Inhibition of human N-terminal His-tagged EZH2/flag-tagged EED/SUZ12/AEBP2/RBAP48 A677G mutant (2 to end residues) expressed in baculovirus infected Sf9 insect cells using histone H3 (1 to 50 residues)-GGK as substrate after 2 hrs in presence of SAM by fluorescence assay	ic50	0.0029	uM
5-ethyl-6-[ethyl(oxan-4-yl)amino]-N-[(4-methoxy-6-methyl-2-oxo-1H-pyridin-3-yl)methyl]-1-benzofuran-4-carboxamide	1350244: Inhibition of human N-terminal His-tagged EZH2/flag-tagged EED/SUZ12/AEBP2/RBAP48 A677G mutant (2 to end residues) expressed in baculovirus infected Sf9 insect cells using histone H3 (1 to 50 residues)-GGK as substrate after 2 hrs in presence of SAM by fluorescence assay	ic50	0.0033	uM
N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-6-[ethyl(oxan-4-yl)amino]-2,5-dimethyl-1-benzofuran-4-carboxamide	1350244: Inhibition of human N-terminal His-tagged EZH2/flag-tagged EED/SUZ12/AEBP2/RBAP48 A677G mutant (2 to end residues) expressed in baculovirus infected Sf9 insect cells using histone H3 (1 to 50 residues)-GGK as substrate after 2 hrs in presence of SAM by fluorescence assay	ic50	0.0038	uM
N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-5-ethyl-6-[ethyl(oxan-4-yl)amino]-2-(1-propan-2-ylpiperidin-4-yl)-1-benzofuran-4-carboxamide	1350244: Inhibition of human N-terminal His-tagged EZH2/flag-tagged EED/SUZ12/AEBP2/RBAP48 A677G mutant (2 to end residues) expressed in baculovirus infected Sf9 insect cells using histone H3 (1 to 50 residues)-GGK as substrate after 2 hrs in presence of SAM by fluorescence assay	ic50	0.0040	uM
6-[ethyl(oxan-4-yl)amino]-N-[(4-methoxy-6-methyl-2-oxo-1H-pyridin-3-yl)methyl]-5-methyl-1-benzofuran-4-carboxamide	1350244: Inhibition of human N-terminal His-tagged EZH2/flag-tagged EED/SUZ12/AEBP2/RBAP48 A677G mutant (2 to end residues) expressed in baculovirus infected Sf9 insect cells using histone H3 (1 to 50 residues)-GGK as substrate after 2 hrs in presence of SAM by fluorescence assay	ic50	0.0040	uM
N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-6-[ethyl(oxan-4-yl)amino]-5-methyl-1-benzofuran-4-carboxamide	1350244: Inhibition of human N-terminal His-tagged EZH2/flag-tagged EED/SUZ12/AEBP2/RBAP48 A677G mutant (2 to end residues) expressed in baculovirus infected Sf9 insect cells using histone H3 (1 to 50 residues)-GGK as substrate after 2 hrs in presence of SAM by fluorescence assay	ic50	0.0040	uM
Tazemetostat	1350244: Inhibition of human N-terminal His-tagged EZH2/flag-tagged EED/SUZ12/AEBP2/RBAP48 A677G mutant (2 to end residues) expressed in baculovirus infected Sf9 insect cells using histone H3 (1 to 50 residues)-GGK as substrate after 2 hrs in presence of SAM by fluorescence assay	ic50	0.0040	uM
6-[ethyl(oxan-4-yl)amino]-2-fluoro-N-[(4-methoxy-6-methyl-2-oxo-1H-pyridin-3-yl)methyl]-5-methyl-1-benzofuran-4-carboxamide	1350244: Inhibition of human N-terminal His-tagged EZH2/flag-tagged EED/SUZ12/AEBP2/RBAP48 A677G mutant (2 to end residues) expressed in baculovirus infected Sf9 insect cells using histone H3 (1 to 50 residues)-GGK as substrate after 2 hrs in presence of SAM by fluorescence assay	ic50	0.0041	uM
N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-5-ethyl-6-[ethyl(oxan-4-yl)amino]-2-(morpholin-4-ylmethyl)-1-benzofuran-4-carboxamide	1350244: Inhibition of human N-terminal His-tagged EZH2/flag-tagged EED/SUZ12/AEBP2/RBAP48 A677G mutant (2 to end residues) expressed in baculovirus infected Sf9 insect cells using histone H3 (1 to 50 residues)-GGK as substrate after 2 hrs in presence of SAM by fluorescence assay	ic50	0.0046	uM
6-[ethyl(oxan-4-yl)amino]-5-methyl-N-[[6-methyl-2-oxo-4-(trifluoromethyl)-1H-pyridin-3-yl]methyl]-1-benzofuran-4-carboxamide	1350244: Inhibition of human N-terminal His-tagged EZH2/flag-tagged EED/SUZ12/AEBP2/RBAP48 A677G mutant (2 to end residues) expressed in baculovirus infected Sf9 insect cells using histone H3 (1 to 50 residues)-GGK as substrate after 2 hrs in presence of SAM by fluorescence assay	ic50	0.0046	uM
6-[ethyl(oxan-4-yl)amino]-N-[(4-methoxy-6-methyl-2-oxo-1H-pyridin-3-yl)methyl]-3,5-dimethyl-1-benzofuran-4-carboxamide	1350244: Inhibition of human N-terminal His-tagged EZH2/flag-tagged EED/SUZ12/AEBP2/RBAP48 A677G mutant (2 to end residues) expressed in baculovirus infected Sf9 insect cells using histone H3 (1 to 50 residues)-GGK as substrate after 2 hrs in presence of SAM by fluorescence assay	ic50	0.0059	uM
N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-6-[ethyl(oxan-4-yl)amino]-5-methyl-1-benzothiophene-4-carboxamide	1350244: Inhibition of human N-terminal His-tagged EZH2/flag-tagged EED/SUZ12/AEBP2/RBAP48 A677G mutant (2 to end residues) expressed in baculovirus infected Sf9 insect cells using histone H3 (1 to 50 residues)-GGK as substrate after 2 hrs in presence of SAM by fluorescence assay	ic50	0.0060	uM
N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-5-ethyl-6-[ethyl(oxan-4-yl)amino]-2-(1-methylpiperidin-4-yl)-1-benzofuran-4-carboxamide	1350244: Inhibition of human N-terminal His-tagged EZH2/flag-tagged EED/SUZ12/AEBP2/RBAP48 A677G mutant (2 to end residues) expressed in baculovirus infected Sf9 insect cells using histone H3 (1 to 50 residues)-GGK as substrate after 2 hrs in presence of SAM by fluorescence assay	ic50	0.0061	uM
5-ethyl-6-[ethyl(oxan-4-yl)amino]-N-[(4-methoxy-6-methyl-2-oxo-1H-pyridin-3-yl)methyl]-2-(piperidin-1-ylmethyl)-1-benzofuran-4-carboxamide	1350244: Inhibition of human N-terminal His-tagged EZH2/flag-tagged EED/SUZ12/AEBP2/RBAP48 A677G mutant (2 to end residues) expressed in baculovirus infected Sf9 insect cells using histone H3 (1 to 50 residues)-GGK as substrate after 2 hrs in presence of SAM by fluorescence assay	ic50	0.0064	uM
5-chloro-6-[ethyl(oxan-4-yl)amino]-N-[(6-methyl-2-oxo-1H-pyridin-3-yl)methyl]-1-benzofuran-4-carboxamide	1350244: Inhibition of human N-terminal His-tagged EZH2/flag-tagged EED/SUZ12/AEBP2/RBAP48 A677G mutant (2 to end residues) expressed in baculovirus infected Sf9 insect cells using histone H3 (1 to 50 residues)-GGK as substrate after 2 hrs in presence of SAM by fluorescence assay	ic50	0.0065	uM
9-bromo-2-[4-(dimethylamino)cyclohexyl]-6-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-2,4-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5-one	1868645: Inhibition of EZH1 (unknown origin)	ic50	0.0070	uM
5-ethyl-6-[ethyl(oxan-4-yl)amino]-N-[(4-methoxy-6-methyl-2-oxo-1H-pyridin-3-yl)methyl]-2-(morpholin-4-ylmethyl)-1-benzofuran-4-carboxamide	1350244: Inhibition of human N-terminal His-tagged EZH2/flag-tagged EED/SUZ12/AEBP2/RBAP48 A677G mutant (2 to end residues) expressed in baculovirus infected Sf9 insect cells using histone H3 (1 to 50 residues)-GGK as substrate after 2 hrs in presence of SAM by fluorescence assay	ic50	0.0078	uM
(2S,4R)-1-[(2S)-2-[[9-[4-[[4-[3-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methylcarbamoyl]-5-[ethyl(oxan-4-yl)amino]-4-methylphenyl]phenyl]methyl]piperazin-1-yl]-9-oxononanoyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	2073634: Displacement of [3H-SAM] from full-length EZH1 (2 to 746 residues) (unknown origin) using a core histone substrate	ic50	0.0086	uM
(2R)-7-chloro-2-[4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide;4-methylbenzenesulfonic acid	2142375: Inhibition of EZH1 (unknown origin) preincubated for 15 mins followed by addition of substrate measured after 1 hr by AlphaLISA assay	ic50	0.0100	uM
6-cyano-N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-1-pentan-3-ylindole-4-carboxamide	1868658: Inhibition of EZH1 (unknown origin) using dimethylated H3K27 as substrate in presence of SAM by biochemical assay	ic50	0.0130	uM
5-bromo-N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-3-[ethyl(oxan-4-yl)amino]-2-methylbenzamide	1350244: Inhibition of human N-terminal His-tagged EZH2/flag-tagged EED/SUZ12/AEBP2/RBAP48 A677G mutant (2 to end residues) expressed in baculovirus infected Sf9 insect cells using histone H3 (1 to 50 residues)-GGK as substrate after 2 hrs in presence of SAM by fluorescence assay	ic50	0.0200	uM
7-bromo-2-[4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide	1854197: Inhibition of EZH1 (unknown origin)	ic50	0.0210	uM
7-chloro-2-[4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide	1854197: Inhibition of EZH1 (unknown origin)	ic50	0.0230	uM
N-[(6-methyl-2-oxo-4-propyl-1H-pyridin-3-yl)methyl]-1-propan-2-yl-6-[6-(4-propan-2-ylpiperazin-1-yl)-3-pyridinyl]-2,3-dihydroindazole-4-carboxamide	1868645: Inhibition of EZH1 (unknown origin)	ic50	0.0450	uM
1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-6-[4-(morpholin-4-ylmethyl)phenyl]indazole-4-carboxamide	1729409: Inhibition of EZH1 in PRC2 complex (unknown origin) using biotinylated peptide as substrate in presence of S-adenosylmethionine	ic50	0.0450	uM
N-[(6-methyl-2-oxo-4-propyl-1H-pyridin-3-yl)methyl]-1-propan-2-yl-6-[6-(4-propan-2-ylpiperazin-1-yl)-3-pyridinyl]indazole-4-carboxamide	2016923: Inhibition of human recombinant full length EZH1 measured after 30 mins by scintillation proximity assay	ic50	0.0450	uM
N-(furan-2-ylmethyl)-8-(4-methylsulfonylphenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine	1802691: HMT Assay from Article 10.1038/nchembio.2304: “An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED.”	ic50	0.0500	uM
N-[(4-methoxy-6-methyl-2-oxo-1H-pyridin-3-yl)methyl]-2-methyl-1-[(1R)-1-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]ethyl]indole-3-carboxamide	1734709: Inhibition of EZH1 (unknown origin)	ic50	0.0520	uM
N-[(6-methyl-2-oxo-4-propyl-1H-pyridin-3-yl)methyl]-6-(6-piperazin-1-yl-3-pyridinyl)-1-propan-2-ylindazole-4-carboxamide	1636820: Inhibition of EZH1 histone methyltransferase activity of EZH1/EED/SUZ12/RBBP4/AEBP2 protein complex (unknown origin) using histone H3 peptide as substrate (21 to 44 residues) in presence of [3H]-S-adenosylmethionine after 2 hrs by scintillation proximity assay	ic50	0.0600	uM
5,8-dichloro-2-[(4-methoxy-6-methyl-2-oxo-1H-pyridin-3-yl)methyl]-7-[(R)-methoxy(oxetan-3-yl)methyl]-3,4-dihydroisoquinolin-1-one	1472381: Binding affinity to EZH1 (unknown origin)	ki	0.0700	uM
1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-3-methyl-6-(6-piperazin-1-yl-3-pyridinyl)indole-4-carboxamide	2191420: Inhibition of EZH1 (unknown origin)	ic50	0.0750	uM
3-[ethyl(oxan-4-yl)amino]-2-methyl-N-[(1-methyl-3-oxo-5,6,7,8-tetrahydro-2H-isoquinolin-4-yl)methyl]-5-[4-(4-methylpiperazin-1-yl)phenyl]benzamide	1868635: Inhibition of wild-type EZH1 (unknown origin) by AlphaLisa assay	ic50	0.0810	uM
3-[ethyl(oxan-4-yl)amino]-2-methyl-N-[(1-methyl-3-oxo-5,6,7,8-tetrahydro-2H-isoquinolin-4-yl)methyl]-5-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]benzamide	1868635: Inhibition of wild-type EZH1 (unknown origin) by AlphaLisa assay	ic50	0.0840	uM
N-[(4-cyclopentyl-6-methyl-2-oxo-1H-pyridin-3-yl)methyl]-1-propan-2-yl-6-[6-(4-propan-2-ylpiperazin-1-yl)-3-pyridinyl]indazole-4-carboxamide	1636820: Inhibition of EZH1 histone methyltransferase activity of EZH1/EED/SUZ12/RBBP4/AEBP2 protein complex (unknown origin) using histone H3 peptide as substrate (21 to 44 residues) in presence of [3H]-S-adenosylmethionine after 2 hrs by scintillation proximity assay	ic50	0.0860	uM
6-[6-(4-ethylpiperazin-1-yl)-3-pyridinyl]-N-[(6-methyl-2-oxo-4-propyl-1H-pyridin-3-yl)methyl]-1-propan-2-ylindazole-4-carboxamide	1636820: Inhibition of EZH1 histone methyltransferase activity of EZH1/EED/SUZ12/RBBP4/AEBP2 protein complex (unknown origin) using histone H3 peptide as substrate (21 to 44 residues) in presence of [3H]-S-adenosylmethionine after 2 hrs by scintillation proximity assay	ic50	0.0880	uM
(2R)-N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-7-[6-(4-ethylpiperazin-1-yl)-3-pyridinyl]-2,4-dimethyl-2-(morpholin-4-ylmethyl)-1,3-benzodioxole-5-carboxamide	1868652: Displacement of [3H]-SAM from EZH1 (unknown origin) using histone H3 as substrate incubated for 2 hrs by cell-free assay	ic50	0.0910	uM
N-[(6-methyl-2-oxo-4-propyl-1H-pyridin-3-yl)methyl]-6-[6-(4-methylpiperazin-1-yl)-3-pyridinyl]-1-propan-2-ylindazole-4-carboxamide	711406: Inhibition of PRC2 complex of EZH1, EED, SUZ12, AEBP2 and RbAp48 using histone H3 peptide (21 to 44) as substrate and [3H]SAM after 1 hr by SPA	ic50	0.1000	uM
1-cyclopentyl-N-[(6-methyl-2-oxo-4-propyl-1H-pyridin-3-yl)methyl]-6-[6-(4-propan-2-ylpiperazin-1-yl)-3-pyridinyl]indazole-4-carboxamide	1636820: Inhibition of EZH1 histone methyltransferase activity of EZH1/EED/SUZ12/RBBP4/AEBP2 protein complex (unknown origin) using histone H3 peptide as substrate (21 to 44 residues) in presence of [3H]-S-adenosylmethionine after 2 hrs by scintillation proximity assay	ic50	0.1080	uM
1-butan-2-yl-N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-3-methyl-6-(6-piperazin-1-yl-3-pyridinyl)indole-4-carboxamide	1967639: Inhibition of EZH1 (unknown origin) by radiometric assay	ic50	0.1240	uM
N-[(6-methyl-2-oxo-4-propyl-1H-pyridin-3-yl)methyl]-1-pentan-3-yl-6-[6-(4-propan-2-ylpiperazin-1-yl)-3-pyridinyl]indazole-4-carboxamide	1636820: Inhibition of EZH1 histone methyltransferase activity of EZH1/EED/SUZ12/RBBP4/AEBP2 protein complex (unknown origin) using histone H3 peptide as substrate (21 to 44 residues) in presence of [3H]-S-adenosylmethionine after 2 hrs by scintillation proximity assay	ic50	0.1260	uM
1-tert-butyl-N-[(6-methyl-2-oxo-4-propyl-1H-pyridin-3-yl)methyl]-6-[6-(4-propan-2-ylpiperazin-1-yl)-3-pyridinyl]indazole-4-carboxamide	1636820: Inhibition of EZH1 histone methyltransferase activity of EZH1/EED/SUZ12/RBBP4/AEBP2 protein complex (unknown origin) using histone H3 peptide as substrate (21 to 44 residues) in presence of [3H]-S-adenosylmethionine after 2 hrs by scintillation proximity assay	ic50	0.1270	uM
3-[cyclohexyl(ethyl)amino]-2-methyl-N-[(1-methyl-3-oxo-5,6,7,8-tetrahydro-2H-isoquinolin-4-yl)methyl]-5-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]benzamide	1868641: Inhibition of EZH1 (unknown origin) by AlphaLisa assay	ic50	0.1365	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	5
sodium arsenite	increases expression, decreases expression, affects cotreatment, increases abundance	3
bisphenol A	affects expression, increases expression	2
Arsenic	increases abundance, increases expression, affects cotreatment, decreases expression	2
Cisplatin	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
trichostatin A	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
beta-glycerophosphoric acid	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
belinostat	increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	increases expression	1
Resveratrol	increases expression	1
Ascorbic Acid	affects cotreatment, increases expression	1
Benzo(a)pyrene	affects methylation	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Ellagic Acid	increases expression	1
Ethyl Methanesulfonate	increases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Mercury	increases expression	1
Nickel	decreases expression	1
Smoke	decreases expression	1

ChEMBL screening assays

67 unique, capped per target: 64 binding, 3 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3399058	Binding	Inhibition of EZH1 (unknown origin) by HMT assay	SAH derived potent and selective EZH2 inhibitors. — Bioorg Med Chem Lett
CHEMBL5723135	Functional	Affinity Biochemical interaction: (ELISA-based protein substrate methylation assay) EUB0002228a EZH1	Affinity Biochemical Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8FP	Abcam HCT 116 EZH1 KO	Cancer cell line	Male
CVCL_B8VJ	Abcam MCF-7 EZH1 KO	Cancer cell line	Female
CVCL_B9HW	Abcam A-549 EZH1 KO	Cancer cell line	Male
CVCL_SM64	HAP1 EZH1 (-) 1	Cancer cell line	Male
CVCL_SM65	HAP1 EZH1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

202 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,
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
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
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice