EHMT1

Summary

EHMT1 (euchromatic histone lysine methyltransferase 1, HGNC:24650) is a protein-coding gene on chromosome 9q34.3, encoding Histone-lysine N-methyltransferase EHMT1 (Q9H9B1). Histone methyltransferase that specifically mono-, di- and trimethylates ‘Lys-9’ of histone H3 (H3K9me1, H3K9me2 and H3K9me3, respectively) in euchromatin.

The protein encoded by this gene is a histone methyltransferase that methylates the lysine-9 position of histone H3. This action marks the genomic region packaged with these methylated histones for transcriptional repression. This protein may be involved in the silencing of MYC- and E2F-responsive genes and therefore could play a role in the G0/G1 cell cycle transition. Defects in this gene are a cause of chromosome 9q subtelomeric deletion syndrome (9q-syndrome, also known as Kleefstra syndrome). Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 79813 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Kleefstra syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 2,554 total — 227 pathogenic, 59 likely-pathogenic
• Phenotypes (HPO): 147
• Druggable target: yes — 5 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_024757

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24650
Approved symbol	EHMT1
Name	euchromatic histone lysine methyltransferase 1
Location	9q34.3
Locus type	gene with protein product
Status	Approved
Aliases	Eu-HMTase1, FLJ12879, KIAA1876, bA188C12.1, KMT1D, FLJ40292, GLP
Ensembl gene	ENSG00000181090
Ensembl biotype	protein_coding
OMIM	607001
Entrez	79813

Gene structure

Transcript identifiers

Ensembl transcripts: 61 — 28 protein_coding, 21 protein_coding_CDS_not_defined, 7 nonsense_mediated_decay, 5 retained_intron

ENST00000371394, ENST00000460486, ENST00000460843, ENST00000462484, ENST00000462942, ENST00000465566, ENST00000472849, ENST00000475564, ENST00000475704, ENST00000478940, ENST00000482340, ENST00000483653, ENST00000486164, ENST00000488242, ENST00000492232, ENST00000493484, ENST00000494249, ENST00000495657, ENST00000626066, ENST00000626216, ENST00000629335, ENST00000629417, ENST00000629808, ENST00000630754, ENST00000635741, ENST00000635783, ENST00000635987, ENST00000636027, ENST00000636081, ENST00000636186, ENST00000636376, ENST00000636463, ENST00000636472, ENST00000636526, ENST00000636565, ENST00000637161, ENST00000637261, ENST00000637277, ENST00000637287, ENST00000637318, ENST00000637335, ENST00000637407, ENST00000637593, ENST00000637655, ENST00000637662, ENST00000637748, ENST00000637784, ENST00000637891, ENST00000637949, ENST00000637977, ENST00000638071, ENST00000640639, ENST00000896761, ENST00000896762, ENST00000896763, ENST00000896764, ENST00000896765, ENST00000896766, ENST00000918861, ENST00000918862, ENST00000918863

RefSeq mRNA: 6 — MANE Select: NM_024757 NM_001145527, NM_001354259, NM_001354263, NM_001354611, NM_001354612, NM_024757

CCDS: CCDS56595, CCDS7050, CCDS87721

Canonical transcript exons

ENST00000460843 — 27 exons

Exon	Start	End
ENSE00001096958	137815947	137816062
ENSE00001096991	137814431	137814508
ENSE00001304607	137834773	137836127
ENSE00003458309	137779635	137779717
ENSE00003479032	137716626	137717182
ENSE00003489145	137710967	137711030
ENSE00003501239	137754171	137754291
ENSE00003526324	137798813	137798914
ENSE00003526599	137813006	137813173
ENSE00003546832	137777882	137778055
ENSE00003548397	137743371	137743528
ENSE00003555463	137811461	137811615
ENSE00003576387	137752331	137752408
ENSE00003605940	137775109	137775252
ENSE00003631340	137818060	137818138
ENSE00003633019	137834349	137834524
ENSE00003633942	137813386	137813530
ENSE00003637059	137728349	137728529
ENSE00003638059	137782291	137782397
ENSE00003640436	137800880	137800984
ENSE00003640812	137776618	137776844
ENSE00003654807	137757880	137758011
ENSE00003664862	137790848	137790970
ENSE00003674730	137817439	137817525
ENSE00003677431	137762675	137762820
ENSE00003689566	137743902	137744090
ENSE00003773100	137619005	137619049

Expression profiles

Bgee: expression breadth ubiquitous, 257 present calls, max score 98.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.6149 / max 185.9827, expressed in 1788 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
99708	12.3598	1787
99712	0.0884	51
99710	0.0464	18
99713	0.0446	30
99711	0.0385	15
99716	0.0254	6
99714	0.0076	3
99715	0.0042	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	98.76	gold quality
adrenal tissue	UBERON:0018303	97.62	gold quality
left testis	UBERON:0004533	96.91	gold quality
right testis	UBERON:0004534	96.75	gold quality
left ovary	UBERON:0002119	95.72	gold quality
body of uterus	UBERON:0009853	95.51	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.48	gold quality
lower esophagus mucosa	UBERON:0035834	95.44	gold quality
skin of leg	UBERON:0001511	95.43	gold quality
granulocyte	CL:0000094	95.37	gold quality
ectocervix	UBERON:0012249	95.32	gold quality
right ovary	UBERON:0002118	95.29	gold quality
skin of abdomen	UBERON:0001416	95.27	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.17	gold quality
right lobe of thyroid gland	UBERON:0001119	95.15	gold quality
tibial nerve	UBERON:0001323	95.12	gold quality
left lobe of thyroid gland	UBERON:0001120	94.98	gold quality
endocervix	UBERON:0000458	94.95	gold quality
mucosa of stomach	UBERON:0001199	94.76	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.72	gold quality
spleen	UBERON:0002106	94.61	gold quality
minor salivary gland	UBERON:0001830	94.53	gold quality
cerebellar hemisphere	UBERON:0002245	94.51	gold quality
left adrenal gland cortex	UBERON:0035825	94.47	gold quality
right adrenal gland cortex	UBERON:0035827	94.40	gold quality
transverse colon	UBERON:0001157	94.37	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.36	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.33	gold quality
cerebellar cortex	UBERON:0002129	94.32	gold quality
right lung	UBERON:0002167	94.32	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-46	yes	49.25
E-ANND-3	yes	9.36
E-CURD-114	yes	8.01
E-MTAB-8060	no	77.12
E-MTAB-6678	no	3.64

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKB1, TP53

miRNA regulators (miRDB)

87 targeting EHMT1, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-12136	99.98	72.81	5713
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-33A-3P	99.70	70.27	3362

Literature-anchored findings (GeneRIF, showing 40)

• This indicates that haploinsufficiency of Eu-HMTase1 is responsible for the 9q submicroscopic subtelomeric deletion syndrome (PMID:15805155)
• Haploinsufficiency of EHMT1 is causative for 9q subtelomeric deletion syndrome. (PMID:16826528)
• G9a and GLP contain a new type of methyllysine binding module (the ankyrin repeat domains) and are the first examples of protein (histone) methyltransferases harboring in a single polypeptide the activities that generate and read the same epigenetic mark. (PMID:18264113)
• Normal head and neck tissues have unique epigenetic profiles demarcated by distinct HKMTase gene expression. (PMID:19128641)
• Seq. analysis of EHMT1 in patients with 9qSTD phenotype without deletion id’d six patients with an intragenic EHMT1 mutation. (PMID:19264732)
• We found robust DNA hypomethylation in G9a/GLP knockdown of murine ES cells but a lack of DNA methylation changes in G9a/GLP knockdown human cancer cells; intriguingly, this distinction also extended to markers of global DNA methylation. (PMID:19531572)
• G9a and Glp methylate lysine 373 in the tumor suppressor p53 (PMID:20118233)
• MDM2 mediates formation of p53-SUV39H1/EHMT1 complex capable of methylating H3-K9 in vitro and on p53 target promoters in vivo. (PMID:20588255)
• the first descriptions of affected parent-to-child transmission of Kleefstra syndrome caused by small interstitial deletions, approximately 200 kb, involving part of the EHMT1 gene. (PMID:21204793)
• These results have important implications for the genetic screening of Kleefstra syndrome and for studies of the functional significance of EHMT1. (PMID:21538692)
• Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability. (PMID:22726846)
• EHMT1 protein binds to nuclear factor-kappaB p50 and represses gene expression. (PMID:22801426)
• Data indicate that Kleefstra syndrome patient carrying a splice-site mutation in EHMT1 inherited from the mother who showed tissue-specific mosaicism. (PMID:23232695)
• Results suggest that GLP may play a significant role in the maintenance of HIV-1 latency by catalyzing dimethylation of H3K9. (PMID:23541084)
• PRC2 and G9a/GLP interact physically and functionally. (PMID:24389103)
• The expression level of EHMT1 and EHMT2 inversely correlates with the type I interferon responsiveness in chronic myeloid leukemia cell lines. (PMID:25079219)
• The current knowledge on the mechanisms of action and function of EHMT1, with particular emphasis on their interplay in the regulation of chromatin states and biological processes. (PMID:25365549)
• Haploinsufficiency of EHMT1 caused by either microdeletions at 9q34.3 or intragenic mutations are associated with Kleefstra syndrome. (PMID:25380126)
• Data indicate zinc finger proteins ZNF644 and WIZ as two core subunits in the histone-lysine N-methyltransferase G9a/GLP complex, and interact with the transcription activation domain of G9a and GLP. (PMID:25789554)
• This study demonstrate that the increases in a restrictive epigenome seen in schizophrenia are sex dependent. Specifically,H3K9me2 were significantly increased in lymphocytes from men with schizophrenia. (PMID:25935252)
• data provide genetic and pharmacologic evidence that EHMT1 and EHMT2 are epigenetic regulators involved in gamma-globin repression and represent a novel therapeutic target for SCD. (PMID:26320100)
• the clinical picture we found in Norwegian patients with Kleefstra syndrome is similar to the findings described in the literature. An interesting point is that in the literature >85% of the patients have a deletion of 9q34.3 and the remaining have a mutation in the EHMT1 gene, whereas in this study we found 50% with a deletion, and 50% with a mutation. (PMID:26808425)
• G9a and GLP are required for stable maintenance of imprinted DNA methylation in embryonic stem cells. (PMID:27052169)
• we find an estrogen receptor-independent synthetic lethal interaction between a GATA3 frameshift mutant with an extended C-terminus and the histone methyltransferases G9A and GLP, indicating perturbed epigenetic regulation (PMID:27588951)
• Selective degradation of the mutant EHMT1 mRNA leads to Kleefstra syndrome. (PMID:27651234)
• Neurodevelopmental disorders may be related to deficits in activity-dependent wiring of brain circuits during development. Although Kleefstra syndrome has been associated with dendritic and synaptic defects in mice and Drosophila, little is known about the role of EHMT1 in the development of cortical neuronal networks. We investigated the impact of EHMT1 deficiency at the network and single cell level. (PMID:27767173)
• missense variants in EHMT1 that lead to protein misfolding and disrupted histone mark binding can lead to Kleefstra Syndrome [case reports] (PMID:28057753)
• These results suggest that EHMT2 downregulation in CD4(+) T-cells may be linked to a protection mechanism against the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). (PMID:28608127)
• Regulated methylation and phosphorylation serve as a switch controlling G9a and GLP coactivator function, suggesting that this mechanism may be a general paradigm for directing specific transcription factor and coregulator actions on different genes. (PMID:28615290)
• trr and G9a also have common direct targets, including the Drosophila ortholog of Arc (Arc1), a key regulator of synaptic plasticity. Our data highlight the clinical and molecular convergence between the KMT2 and EHMT protein families, which may contribute to a molecular network underlying a larger group of intellectual disability / autism spectrum disorder -related disorders. (PMID:29069077)
• High GLP expression is associated with Ovarian Cancer metastasis. (PMID:29259012)
• The Autism spectrum disorder candidate genes SATB2, CHD8 and EHMT1 show enriched expression in neurons, especially inhibitory neurons (PMID:29317598)
• Individuals with EHMT1 mosaicism seem to have increased vulnerability for developing severe psychopathology, especially ASD and mood disorders. (PMID:29416845)
• our biochemical characterization clearly demonstrates that the previously reported two missense mutations of EHMT1 deteriorate HMT activity and GLP function, which presumably cause KS. (PMID:29459631)
• In summary, it was demonstrated here that the overexpression of GLP is associated with a worse prognosis in Chronic Lymphocytic Leukemia (CLL) and that the inhibition of GLP/G9a complex leads to CLL cell death. These results suggest a potential use for GLP/G9a as markers for disease progression, as well as a promising epigenetic target for CLL treatment and prevention of disease evolution. (PMID:29855824)
• G9a and GLP directly bound to the alpha subunit of HIF-1 (HIF-1alpha) and catalyzed mono- and di-methylation of HIF-1alpha. The methylation suppressed HIF-1 transcriptional activity (PMID:29860315)
• We report infantile onset Pulmonary hypertension (PH) and congenital heart disease despite early CHD repair in three unrelated children with Kleefstra syndrome with deletions at 9q34.3 and define a 1.24 Mb critical region containing 47 protein-coding RefSeq genes including EHMT1. (PMID:30063093)
• 9q34.3 microduplications lead to neurodevelopmental disorders through EHMT1 overexpression. (PMID:31209758)
• Neuronal networks of Kleefstra syndrome patient-derived cells exhibit network bursting with a reduced rate, longer duration, and increased temporal irregularity compared to control networks. We show that these changes are mediated by upregulation of NMDA receptor (NMDAR) subunit 1 correlating with reduced deposition of the repressive H3K9me2 mark, the catalytic product of EHMT1, at the GRIN1 promoter. (PMID:31666522)
• The authors show that IFI16 is in complex with the H3K9 methyltransferase SUV39H1 and GLP and recruits them to the human herpesvirus 8 genome during de novo infection and latency. The resulting depositions of H3K9me2/me3 serve as a docking site for the heterochromatin-inducing HP1alpha protein leading into the IFI16-dependent epigenetic modifications and silencing of the virus lytic genes. (PMID:31682228)

Cross-species orthologs

18 orthologs

Organism	Symbol	Gene ID
danio_rerio	ehmt1b	ENSDARG00000026634
danio_rerio	ehmt1a	ENSDARG00000068157
mus_musculus	Ehmt1	ENSMUSG00000036893
rattus_norvegicus	Ehmt1	ENSRNOG00000007242
drosophila_melanogaster	ash1	FBGN0005386
drosophila_melanogaster	Set2	FBGN0030486
drosophila_melanogaster	CG4565	FBGN0037841
drosophila_melanogaster	G9a	FBGN0040372
caenorhabditis_elegans	set-32	WBGENE00008062
caenorhabditis_elegans		WBGENE00008206
caenorhabditis_elegans		WBGENE00008527
caenorhabditis_elegans	met-1	WBGENE00016603
caenorhabditis_elegans		WBGENE00018023
caenorhabditis_elegans		WBGENE00019584
caenorhabditis_elegans		WBGENE00019690
caenorhabditis_elegans		WBGENE00020006
caenorhabditis_elegans		WBGENE00020919
caenorhabditis_elegans		WBGENE00021282

Paralogs (19): KMT2C (ENSG00000055609), SETD1A (ENSG00000099381), SUV39H1 (ENSG00000101945), EZH2 (ENSG00000106462), EZH1 (ENSG00000108799), NSD2 (ENSG00000109685), ASH1L (ENSG00000116539), KMT2A (ENSG00000118058), SETDB2 (ENSG00000136169), SETD1B (ENSG00000139718), SETDB1 (ENSG00000143379), NSD3 (ENSG00000147548), SETBP1 (ENSG00000152217), SUV39H2 (ENSG00000152455), NSD1 (ENSG00000165671), KMT2D (ENSG00000167548), SETD2 (ENSG00000181555), EHMT2 (ENSG00000204371), KMT2B (ENSG00000272333)

Protein

Protein identifiers

Histone-lysine N-methyltransferase EHMT1 — Q9H9B1 (reviewed: Q9H9B1)

Alternative names: Euchromatic histone-lysine N-methyltransferase 1, G9a-like protein 1, Histone H3-K9 methyltransferase 5, Lysine N-methyltransferase 1D

All UniProt accessions (23): A0A0C4DGF8, A0A0D9SEP2, A0A0D9SEQ1, A0A0D9SER3, A0A0D9SER9, A0A0D9SEY2, Q9H9B1, A0A0D9SF38, A0A0D9SFD7, A0A0D9SFG7, A0A0D9SFM6, A0A0D9SFS4, A0A0D9SFX4, A0A1B0GTP4, A0A1B0GU48, A0A1B0GUD1, A0A1B0GV09, A0A1B0GV89, A0A1B0GVZ8, A0A1B0GW12, A0A1B0GW79, A0A1B0GWF6, A0A1W2PPZ7

UniProt curated annotations — full annotation on UniProt →

Function. Histone methyltransferase that specifically mono-, di- and trimethylates ‘Lys-9’ of histone H3 (H3K9me1, H3K9me2 and H3K9me3, respectively) in euchromatin. H3K9me represents a specific tag for epigenetic transcriptional repression by recruiting HP1 proteins to methylated histones. Also weakly methylates ‘Lys-27’ of histone H3 (H3K27me). Also required for DNA methylation, the histone methyltransferase activity is not required for DNA methylation, suggesting that these 2 activities function independently. Probably targeted to histone H3 by different DNA-binding proteins like E2F6, MGA, MAX and/or DP1. During G0 phase, it probably contributes to silencing of MYC- and E2F-responsive genes, suggesting a role in G0/G1 transition in cell cycle. Involved in the differentiation of myoblastic precursors into brown adipose cells: following recruitment to chromatin by PRDM16, mediates formation of H3K9me2 and H3K9me3, inhibiting the expression of white adipose-selective genes. Also involved in the differentiation of beige adipocytes from white adipose cells following recruitment by PRDM16. EHMT1 also promotes protein stabilization of PRDM16, by preventing PRDM16 ubiquitination and degradation. In addition to the histone methyltransferase activity, also methylates non-histone proteins: mediates dimethylation of ‘Lys-373’ of p53/TP53. Represses the expression of mitochondrial function-related genes, perhaps by occupying their promoter regions, working in concert with probable chromatin reader BAZ2B.

Subunit / interactions. Heterodimer; heterodimerizes with EHMT2. Interacts with WIZ and EHMT2. Part of the E2F6.com-1 complex in G0 phase composed of E2F6, MGA, MAX, TFDP1, CBX3, BAT8, EHMT1, RING1, RNF2, MBLR, L3MBTL2 and YAF2. Interacts (via ANK repeats) with RELA (when monomethylated at ‘Lys-310’). Interacts with MPHOSPH8. Interacts with CDYL. Interacts with REST only in the presence of CDYL. Part of a complex containing at least CDYL, REST, WIZ, SETB1, EHMT1 and EHMT2. Interacts with BAZ2B. Interacts with PRDM16; promoting EHMT1 recruitment to chromatin, differentiation of brown adipose cells and stabilization of PRDM16.

Subcellular location. Nucleus. Chromosome.

Tissue specificity. Widely expressed.

Disease relevance. Kleefstra syndrome 1 (KLEFS1) [MIM:610253] A form of Kleefstra syndrome, an autosomal dominant disease characterized by variable intellectual disability, psychomotor developmental delay, seizures, behavioral abnormalities, and facial dysmorphisms. KLEFS1 patients additionally manifest brachy(micro)cephaly, congenital heart defects, and urogenital defects. The disease is caused by variants affecting the gene represented in this entry. The syndrome can be either caused by intragenic EHMT1 mutations leading to haploinsufficiency of the EHMT1 gene or by a submicroscopic 9q34.3 deletion. Although it is not known if and to what extent other genes in the 9q34.3 region contribute to the syndrome observed in deletion cases, EHMT1 seems to be the major determinant of the core disease phenotype.

Activity regulation. Methyltransferase activity is inhibited by BIX-01294. Efficiently inhibited by compound E72, a BIX-01294 derivative in which the diazepane ring and the benzyl are replaced with a 3-dimethylaminopropyl and a 5-aminopentyl group at sites B and C, respectively.

Domain organisation. The ANK repeats specifically recognize and bind H3K9me1 and H3K9me2. They also specifically recognize and bind RELA subunit of NF-kappa-B, when RELA is monomethylated at ‘Lys-310’. The SET domain mediates interaction with WIZ. In the pre-SET domain, Cys residues bind 3 zinc ions that are arranged in a triangular cluster; some of these Cys residues contribute to the binding of two zinc ions within the cluster.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the class V-like SAM-binding methyltransferase superfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9H9B1-1	1	yes
Q9H9B1-2	2
Q9H9B1-3	3
Q9H9B1-4	4

RefSeq proteins (6): NP_001138999, NP_001341188, NP_001341192, NP_001341540, NP_001341541, NP_079033* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001214	SET_dom	Domain
IPR002110	Ankyrin_rpt	Repeat
IPR007728	Pre-SET_dom	Domain
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR038035	SET_EHMT1	Domain
IPR043550	EHMT1/EHMT2	Family
IPR046341	SET_dom_sf	Homologous_superfamily
IPR047762	EHMT_CRR	Domain

Pfam: PF00856, PF05033, PF12796, PF13637, PF21533

Enzyme classification (BRENDA):

• EC 2.1.1.367 — [histone H3]-lysine9 N-methyltransferase (BRENDA: 5 organisms, 4 substrates, 19 inhibitors, 0 Km, 0 kcat entries)
• EC 2.1.1.368 — [histone H3]-lysine9 N-dimethyltransferase (BRENDA: 6 organisms, 10 substrates, 20 inhibitors, 8 Km, 8 kcat entries)

Substrate kinetics (BRENDA)

3 substrates with measured Km, best-characterized 3. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
S-ADENOSYL-L-METHIONINE	0.53–0.68	4
[HISTONE H3 PEPTIDE 1-15]-L-LYSINE9	0.28–0.41	2
[HISTONE H3 PEPTIDE 1-15]-N6-METHYL-L-LYSINE9	0.41–0.59	2

Catalyzed reactions (Rhea), 3 shown:

• L-lysyl(9)-[histone H3] + S-adenosyl-L-methionine = N(6)-methyl-L-lysyl(9)-[histone H3] + S-adenosyl-L-homocysteine + H(+) (RHEA:60280)
• N(6)-methyl-L-lysyl(9)-[histone H3] + S-adenosyl-L-methionine = N(6),N(6)-dimethyl-L-lysyl(9)-[histone H3] + S-adenosyl-L-homocysteine + H(+) (RHEA:60284)
• N(6),N(6)-dimethyl-L-lysyl(9)-[histone H3] + S-adenosyl-L-methionine = N(6),N(6),N(6)-trimethyl-L-lysyl(9)-[histone H3] + S-adenosyl-L-homocysteine + H(+) (RHEA:60288)

UniProt features (132 total): helix 22, binding site 20, strand 19, cross-link 15, compositionally biased region 10, region of interest 9, repeat 8, splice variant 6, modified residue 5, sequence variant 4, mutagenesis site 4, turn 3, domain 2, sequence conflict 2, initiator methionine 1, chain 1, site 1

Structure

Experimental structures (PDB)

23 structures.

PDB	Method	Resolution (Å)
9YKR	X-RAY DIFFRACTION	1.38
3HNA	X-RAY DIFFRACTION	1.5
2RFI	X-RAY DIFFRACTION	1.59
6MBO	X-RAY DIFFRACTION	1.59
5TTG	X-RAY DIFFRACTION	1.66
5VSF	X-RAY DIFFRACTION	1.7
5V9J	X-RAY DIFFRACTION	1.74
5VSD	X-RAY DIFFRACTION	1.85
4I51	X-RAY DIFFRACTION	1.9
6MBP	X-RAY DIFFRACTION	1.95
5TUZ	X-RAY DIFFRACTION	1.95
2IGQ	X-RAY DIFFRACTION	2
3MO5	X-RAY DIFFRACTION	2.14
6BY9	X-RAY DIFFRACTION	2.3
3SWC	X-RAY DIFFRACTION	2.33
3FPD	X-RAY DIFFRACTION	2.4
3MO2	X-RAY DIFFRACTION	2.49
3MO0	X-RAY DIFFRACTION	2.78
7T7M	X-RAY DIFFRACTION	2.85
3B7B	X-RAY DIFFRACTION	2.99
3B95	X-RAY DIFFRACTION	2.99
3SW9	X-RAY DIFFRACTION	3.05
8XPT	X-RAY DIFFRACTION	3.35

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H9B1-F1	64.89	0.36

Functional residue map

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

Catalytic / active sites (1): 1155 (histone h3k9me binding)

Ligand- & substrate-binding residues (20): 1062; 1062; 1064; 1068; 1068; 1073; 1075; 1105; 1105; 1109; 1111; 1115 …

Post-translational modifications (20): 2, 435, 483, 1004, 1048, 22, 22, 190, 199, 231, 234, 317, 327, 432, 492, 559, 644, 659, 684, 731

Mutagenesis-validated functional residues (4):

Position	Phenotype
874	abolishes binding to methylated rela k310me1, histone h3k9me1 and h3k9me2.
882	abolishes binding to methylated rela k310me1, histone h3k9me1 and h3k9me2.
905	abolishes binding to histone h3k9me.
912	abolishes binding to methylated rela k310me1, histone h3k9me1 and h3k9me2.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-2559582	Senescence-Associated Secretory Phenotype (SASP)
R-HSA-3214841	PKMTs methylate histone lysines
R-HSA-6804760	Regulation of TP53 Activity through Methylation
R-HSA-8853884	Transcriptional Regulation by VENTX
R-HSA-8953750	Transcriptional Regulation by E2F6
R-HSA-9843970	Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex

MSigDB gene sets: 463 (showing top): GCACCTT_MIR18A_MIR18B, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_WHITE_FAT_CELL_DIFFERENTIATION, ATGCAGT_MIR217, BILD_SRC_ONCOGENIC_SIGNATURE, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, GOBP_PEPTIDYL_LYSINE_MODIFICATION, GOBP_DNA_METHYLATION_DEPENDENT_CONSTITUTIVE_HETEROCHROMATIN_FORMATION, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, WANG_LMO4_TARGETS_DN, GOBP_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION, GOBP_PROTEIN_STABILIZATION, WTGAAAT_UNKNOWN

GO Biological Process (16): negative regulation of transcription by RNA polymerase II (GO:0000122), chromatin organization (GO:0006325), DNA methylation-dependent constitutive heterochromatin formation (GO:0006346), peptidyl-lysine monomethylation (GO:0018026), peptidyl-lysine dimethylation (GO:0018027), epigenetic regulation of gene expression (GO:0040029), negative regulation of DNA-templated transcription (GO:0045892), regulation of embryonic development (GO:0045995), brown fat cell differentiation (GO:0050873), response to fungicide (GO:0060992), positive regulation of cold-induced thermogenesis (GO:0120162), facultative heterochromatin formation (GO:0140718), beige fat cell differentiation (GO:0160274), negative regulation of white fat cell differentiation (GO:0160275), chromatin remodeling (GO:0006338), methylation (GO:0032259)

GO Molecular Function (16): transcription corepressor binding (GO:0001222), p53 binding (GO:0002039), methyltransferase activity (GO:0008168), zinc ion binding (GO:0008270), protein-lysine N-methyltransferase activity (GO:0016279), histone H3K9 methyltransferase activity (GO:0046974), histone H3K27 methyltransferase activity (GO:0046976), C2H2 zinc finger domain binding (GO:0070742), histone H3K9me2 methyltransferase activity (GO:0140947), histone H3K9 monomethyltransferase activity (GO:0140948), histone H3K9 trimethyltransferase activity (GO:0140949), protein binding (GO:0005515), transferase activity (GO:0016740), histone methyltransferase activity (GO:0042054), metal ion binding (GO:0046872), histone H3 methyltransferase activity (GO:0140938)

GO Cellular Component (6): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), nuclear body (GO:0016604), chromosome (GO:0005694), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Generic Transcription Pathway	2
Cellular Senescence	1
Chromatin modifying enzymes	1
Regulation of TP53 Activity	1
Regulation of endogenous retroelements	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
histone H3K9 methyltransferase activity	3
cellular anatomical structure	3
peptidyl-lysine methylation	2
fat cell differentiation	2
protein methyltransferase activity	2
protein-lysine N-methyltransferase activity	2
histone H3 methyltransferase activity	2
intracellular membraneless organelle	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
cellular component organization	1
constitutive heterochromatin formation	1
chromatin remodeling	1
regulation of gene expression	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
embryo development	1
regulation of multicellular organismal development	1
response to toxic substance	1
response to antibiotic	1
positive regulation of multicellular organismal process	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	1
heterochromatin formation	1
negative regulation of fat cell differentiation	1
white fat cell differentiation	1
chromatin organization	1
metabolic process	1
transcription coregulator binding	1
protein binding	1
transferase activity, transferring one-carbon groups	1
transition metal ion binding	1
lysine N-methyltransferase activity	1
protein domain specific binding	1
binding	1
catalytic activity	1
histone modifying activity	1
cation binding	1

Protein interactions and networks

STRING

3159 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EHMT1	EHMT2	Q96KQ7	979
EHMT1	PRDM16	Q9HAZ2	959
EHMT1	CDYL	Q9Y232	894
EHMT1	HDAC1	Q13547	889
EHMT1	DNMT1	P26358	826
EHMT1	OLFM1	Q99784	817
EHMT1	RCOR1	Q9UKL0	781
EHMT1	E2F6	O75461	751
EHMT1	KDM1A	O60341	737
EHMT1	HDAC2	Q92769	721
EHMT1	WIZ	O95785	699
EHMT1	MECP2	P51608	683
EHMT1	CACNA1B	Q00975	680
EHMT1	HLCS	P50747	651
EHMT1	SETDB1	Q15047	637

IntAct

171 interactions, top by confidence:

A	B	Type	Score
HDAC2	KDM1A	psi-mi:“MI:0914”(association)	0.890
CDK8	MED19	psi-mi:“MI:2364”(proximity)	0.850
HDAC1	CDK2AP1	psi-mi:“MI:0914”(association)	0.840
HDAC1	TNRC18	psi-mi:“MI:0914”(association)	0.790
COPRS	PRMT5	psi-mi:“MI:0914”(association)	0.770
EHMT2	WIZ	psi-mi:“MI:0914”(association)	0.730
CTBP1	CBX4	psi-mi:“MI:0914”(association)	0.700
NFIC	NFIB	psi-mi:“MI:2364”(proximity)	0.690
Rela	EHMT1	psi-mi:“MI:0407”(direct interaction)	0.680
EHMT1	Rela	psi-mi:“MI:0407”(direct interaction)	0.680
Rela	EHMT1	psi-mi:“MI:0915”(physical association)	0.680
H2BC1	PPM1G	psi-mi:“MI:0914”(association)	0.640
MPHOSPH8	EHMT1	psi-mi:“MI:0915”(physical association)	0.560
EHMT1	MPHOSPH8	psi-mi:“MI:0915”(physical association)	0.560
MAD2L2	CBX5	psi-mi:“MI:0914”(association)	0.530
XAGE2	WIZ	psi-mi:“MI:0914”(association)	0.530
CBX1	ZNF292	psi-mi:“MI:0914”(association)	0.530
CBX5	WIZ	psi-mi:“MI:0914”(association)	0.530
SUV39H1	MAGEC1	psi-mi:“MI:0914”(association)	0.530
ZNF462	WIZ	psi-mi:“MI:0914”(association)	0.530
XAGE3	WIZ	psi-mi:“MI:0914”(association)	0.530
MIER2	WIZ	psi-mi:“MI:0914”(association)	0.530

BioGRID (260): PRDM6 (Affinity Capture-Western), EHMT1 (Affinity Capture-MS), EHMT1 (Affinity Capture-MS), EHMT1 (Affinity Capture-MS), EHMT1 (Affinity Capture-MS), EHMT1 (Affinity Capture-MS), EHMT1 (Affinity Capture-MS), EHMT1 (Affinity Capture-MS), EHMT1 (Co-fractionation), EHMT1 (Co-fractionation), EHMT1 (Affinity Capture-MS), EHMT1 (Affinity Capture-MS), EHMT1 (Affinity Capture-MS), EHMT1 (Affinity Capture-MS), EHMT1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D5NS60, A0JN76, A1YFX5, A2T7G6, A6NJL1, D2HQI1, F1MJR8, O14901, P0CG00, P10754, P22227, P98182, Q0IJ29, Q1L8W0, Q3SWU4, Q5DW34, Q5EAC5, Q5EXX3, Q5RHB5, Q5SXI5, Q5T619, Q66H04, Q6NRM8, Q6NV66, Q6ZSB9, Q7M6U3, Q7TS63, Q7TSH3, Q7ZWZ4, Q801P1, Q86VK4, Q8BKX7, Q8BXX2, Q8NAM6, Q8NAP3, Q8NCP5, Q8R0A2, Q91VW9, Q96IT1, Q96N77

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

1 interactions.

A	Effect	B	Mechanism
2-cyclohexyl-6-methoxy-N-(1-propan-2-yl-4-piperidinyl)-7-[3-(1-pyrrolidinyl)propoxy]-4-quinazolinamine	“down-regulates activity”	EHMT1	“chemical inhibition”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 193 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
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	5	11.1×	3e-03
SPOP-mediated proteasomal degradation of PD-L1(CD274)	6	10.2×	1e-03
Negative Regulation of CDH1 Gene Transcription	11	9.8×	9e-06
PKMTs methylate histone lysines	8	9.5×	3e-04
ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression	8	9.0×	3e-04
Deactivation of the beta-catenin transactivating complex	5	8.6×	5e-03
SARS-CoV-1-host interactions	6	7.8×	3e-03
NuRD complex assembly	7	7.3×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
neuron fate specification	5	19.8×	5e-04
heterochromatin formation	12	17.3×	1e-09
negative regulation of gene expression, epigenetic	7	15.9×	3e-05
negative regulation of proteasomal ubiquitin-dependent protein catabolic process	5	11.3×	6e-03
epigenetic regulation of gene expression	5	10.8×	7e-03
positive regulation of miRNA transcription	6	9.8×	3e-03
chromatin remodeling	16	6.6×	6e-07
chromatin organization	11	6.2×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

2554 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	227
Likely pathogenic	59
Uncertain significance	685
Likely benign	1025
Benign	234

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012851	NM_024757.5(EHMT1):c.2498del (p.Asp833fs)	Pathogenic
1031404	NM_024757.5(EHMT1):c.3000del (p.Asp1001fs)	Pathogenic
1048612	NM_024757.5(EHMT1):c.1502-2A>G	Pathogenic
1073971	NC_000009.11:g.(?140646763)(140729425_?)del	Pathogenic
1074863	NM_024757.5(EHMT1):c.2825dup (p.Leu943fs)	Pathogenic
1076531	NM_024757.5(EHMT1):c.2161del (p.Glu721fs)	Pathogenic
1285209	NM_024757.5(EHMT1):c.2929C>T (p.Gln977Ter)	Pathogenic
1285440	NM_024757.5(EHMT1):c.3012_3016del (p.Pro1005fs)	Pathogenic
1285498	NM_024757.5(EHMT1):c.575_581del (p.Pro192fs)	Pathogenic
1285594	NM_024757.5(EHMT1):c.1501+1del	Pathogenic
1314969	NM_024757.5(EHMT1):c.642+1G>C	Pathogenic
1319616	NM_024757.5(EHMT1):c.1408C>T (p.Gln470Ter)	Pathogenic
1352642	NM_024757.5(EHMT1):c.784C>T (p.Gln262Ter)	Pathogenic
1391038	NM_024757.5(EHMT1):c.3482C>G (p.Ser1161Ter)	Pathogenic
1394346	NM_024757.5(EHMT1):c.3393C>A (p.Tyr1131Ter)	Pathogenic
1431672	NM_024757.5(EHMT1):c.162del (p.Asn55fs)	Pathogenic
1453870	NM_024757.5(EHMT1):c.3579del (p.Asn1194fs)	Pathogenic
1459627	NC_000009.11:g.(?140513481)(140513521_?)del	Pathogenic
1684279	NM_024757.5(EHMT1):c.2625del (p.Pro876_Met877insTer)	Pathogenic
1685762	NM_024757.5(EHMT1):c.1292_1296del (p.Gly431fs)	Pathogenic
1685763	NM_024757.5(EHMT1):c.2018+1G>A	Pathogenic
1685764	NM_024757.5(EHMT1):c.3310G>T (p.Glu1104Ter)	Pathogenic
1708114	NM_024757.5(EHMT1):c.2799del (p.His933fs)	Pathogenic
1709546	NM_024757.5(EHMT1):c.294_297del (p.Arg99fs)	Pathogenic
1759153	NM_024757.5(EHMT1):c.749_750delinsG (p.Leu250fs)	Pathogenic
1791947	NM_024757.5(EHMT1):c.2483_2488delinsGA (p.Ala828fs)	Pathogenic
1802603	NM_024757.5(EHMT1):c.3332G>C (p.Cys1111Ser)	Pathogenic
1933541	NM_024757.5(EHMT1):c.2995del (p.Ala999fs)	Pathogenic
2002587	NM_024757.5(EHMT1):c.1800dup (p.Met601fs)	Pathogenic
2026959	NM_024757.5(EHMT1):c.719dup (p.Asn240fs)	Pathogenic

SpliceAI

7409 predictions. Top by Δscore:

Variant	Effect	Δscore
9:137619046:CGAGG:C	donor_loss	1.0000
9:137619047:GAG:G	donor_gain	1.0000
9:137619048:AGGTG:A	donor_loss	1.0000
9:137619050:GTG:G	donor_loss	1.0000
9:137716624:A:AG	acceptor_gain	1.0000
9:137716625:G:GG	acceptor_gain	1.0000
9:137716625:GA:G	acceptor_gain	1.0000
9:137744087:GAAG:G	donor_gain	1.0000
9:137744089:AGGTA:A	donor_loss	1.0000
9:137744090:GGTA:G	donor_loss	1.0000
9:137744091:G:A	donor_loss	1.0000
9:137744092:T:A	donor_loss	1.0000
9:137752299:T:TA	acceptor_gain	1.0000
9:137752300:G:A	acceptor_gain	1.0000
9:137754160:T:TA	acceptor_gain	1.0000
9:137754170:GA:G	acceptor_gain	1.0000
9:137757951:G:GT	donor_gain	1.0000
9:137762821:G:GG	donor_gain	1.0000
9:137773778:GCT:G	donor_gain	1.0000
9:137775107:A:AG	acceptor_gain	1.0000
9:137775107:AGTT:A	acceptor_gain	1.0000
9:137775107:AGTTG:A	acceptor_gain	1.0000
9:137775108:G:GC	acceptor_gain	1.0000
9:137775108:GT:G	acceptor_gain	1.0000
9:137775108:GTT:G	acceptor_gain	1.0000
9:137775108:GTTG:G	acceptor_gain	1.0000
9:137775108:GTTGG:G	acceptor_gain	1.0000
9:137775250:GCG:G	donor_gain	1.0000
9:137775253:G:GG	donor_gain	1.0000
9:137775254:T:G	donor_loss	1.0000

AlphaMissense

8575 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:137762731:T:C	C520R	1.000
9:137762733:C:G	C520W	1.000
9:137762737:T:C	C522R	1.000
9:137762791:T:A	C540S	1.000
9:137762791:T:C	C540R	1.000
9:137762792:G:A	C540Y	1.000
9:137762792:G:C	C540S	1.000
9:137762792:G:T	C540F	1.000
9:137762793:C:G	C540W	1.000
9:137775118:T:A	C553S	1.000
9:137775118:T:C	C553R	1.000
9:137775119:G:C	C553S	1.000
9:137775120:C:G	C553W	1.000
9:137775182:T:C	L574P	1.000
9:137775184:T:A	C575S	1.000
9:137775184:T:C	C575R	1.000
9:137775185:G:A	C575Y	1.000
9:137775185:G:C	C575S	1.000
9:137775185:G:T	C575F	1.000
9:137775186:T:G	C575W	1.000
9:137775197:G:C	R579P	1.000
9:137775223:T:C	C588R	1.000
9:137775224:G:A	C588Y	1.000
9:137775225:T:G	C588W	1.000
9:137775244:T:C	C595R	1.000
9:137775246:C:G	C595W	1.000
9:137776633:T:C	C603R	1.000
9:137776657:C:G	H611D	1.000
9:137776705:T:C	C627R	1.000
9:137776707:T:G	C627W	1.000

dbSNP variants (sampled 300 via entrez): RS1000002350 (9:137714109 C>G), RS1000014700 (9:137748932 A>G), RS1000027532 (9:137772385 C>A,G,T), RS1000029366 (9:137833353 A>G), RS1000054038 (9:137676419 G>A), RS1000070398 (9:137719405 C>T), RS1000082505 (9:137755512 G>A), RS1000094074 (9:137790483 G>A), RS1000100192 (9:137681634 C>A), RS1000125263 (9:137671896 G>T), RS1000131126 (9:137734064 C>G,T), RS1000135155 (9:137719885 G>A), RS1000143504 (9:137685069 G>A,T), RS1000157965 (9:137675429 G>A), RS1000180461 (9:137692149 G>C)

Disease associations

OMIM: gene MIM:607001 | disease phenotypes: MIM:610253, MIM:209850, MIM:181500

GenCC curated gene-disease

Disease	Classification	Inheritance
Kleefstra syndrome 1	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Kleefstra syndrome	Definitive	AD

Mondo (9): Kleefstra syndrome 1 (MONDO:0027407), neurodevelopmental disorder (MONDO:0700092), autism (MONDO:0005260), Kleefstra syndrome (MONDO:0012455), autism spectrum disorder (MONDO:0005258), intellectual disability (MONDO:0001071), polymicrogyria (MONDO:0000087), schizophrenia (MONDO:0005090), epilepsy (MONDO:0005027)

Orphanet (5): Kleefstra syndrome (Orphanet:261494), Polymicrogyria (Orphanet:35981), NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

147 total (30 of 147 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000035	Abnormal testis morphology
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000074	Ureteropelvic junction obstruction
HP:0000076	Vesicoureteral reflux
HP:0000077	Abnormality of the kidney
HP:0000078	Abnormality of the genital system
HP:0000083	Renal insufficiency
HP:0000098	Tall stature
HP:0000107	Renal cyst
HP:0000126	Hydronephrosis
HP:0000158	Macroglossia
HP:0000164	Abnormality of the dentition
HP:0000179	Thick lower lip vermilion
HP:0000232	Everted lower lip vermilion
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000272	Malar flattening
HP:0000280	Coarse facial features
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000365	Hearing impairment
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000519	Developmental cataract
HP:0000540	Hypermetropia

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST007994_19	Asthma (age of onset)	3.000000e-08
GCST007995_55	Asthma (childhood onset)	4.000000e-09
GCST009391_711	Metabolite levels	1.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010531	S-adenosylhomocysteine measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D004827	Epilepsy	C10.228.140.490
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
D065706	Polymicrogyria	C10.500.507.500.500; C16.131.666.507.500.500
C563043	Kleefstra Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL3885593 (PROTEIN FAMILY), CHEMBL5739542 (PROTEIN-PROTEIN INTERACTION), CHEMBL6031 (SINGLE PROTEIN), CHEMBL6066146 (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: 145,386 (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
CHEMBL964	DISULFIRAM	4	38,611
CHEMBL51085	EBSELEN	3	13,237
CHEMBL107217	DITIOCARB SODIUM	2	12,033
CHEMBL120563	THIRAM	2	79,340
CHEMBL1214186	SINEFUNGIN	2	2,165

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
UNC0642	Inhibition	8.6	pIC50
A-366	Inhibition	8.52	pIC50
UNC0638	Inhibition	7.72	pIC50
BIX-01294	Inhibition	4.42	pIC50

ChEMBL bioactivities

241 potent at pChembl≥5 of 264 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.15	IC50	0.7	nM	CHEMBL4162206
8.89	IC50	1.3	nM	CHEMBL5191361
8.80	IC50	1.6	nM	CHEMBL5171820
8.55	IC50	2.8	nM	CHEMBL2441082
8.40	IC50	4	nM	CHEMBL578227
8.40	IC50	4	nM	CHEMBL4094717
8.30	IC50	5	nM	CHEMBL4072211
8.30	IC50	5	nM	CHEMBL5410724
8.22	IC50	6	nM	CHEMBL4066769
8.22	IC50	6	nM	CHEMBL4100004
8.22	IC50	6	nM	CHEMBL4582775
8.15	IC50	7	nM	CHEMBL4086403
8.10	IC50	8	nM	CHEMBL4170114
8.05	IC50	9	nM	CHEMBL4461224
8.05	IC50	9	nM	CHEMBL4467219
8.04	IC50	9.2	nM	CHEMBL5201140
7.96	IC50	11	nM	CHEMBL4085546
7.96	IC50	11	nM	CHEMBL4088064
7.96	IC50	11	nM	CHEMBL576260
7.96	IC50	11	nM	CHEMBL4568910
7.96	IC50	11	nM	CHEMBL3109630
7.96	IC50	11	nM	CHEMBL5182385
7.96	IC50	11	nM	CHEMBL5204152
7.92	IC50	12	nM	CHEMBL570120
7.92	IC50	12	nM	CHEMBL4063569
7.92	IC50	12	nM	CHEMBL4093293
7.92	IC50	12	nM	CHEMBL4464846
7.92	IC50	12	nM	CHEMBL4532743
7.89	IC50	13	nM	CHEMBL571717
7.89	IC50	13	nM	CHEMBL1231795
7.83	IC50	14.7	nM	CHEMBL4795328
7.82	IC50	15	nM	CHEMBL4072569
7.82	IC50	15	nM	CHEMBL1214066
7.82	Ki	15	nM	CHEMBL1214066
7.80	IC50	16	nM	CHEMBL4097286
7.80	IC50	16	nM	CHEMBL4460703
7.80	Kd	16	nM	CHEMBL5189737
7.77	IC50	17	nM	CHEMBL4074209
7.75	IC50	18	nM	CHEMBL4081938
7.75	IC50	18	nM	CHEMBL4084508
7.75	IC50	18	nM	CHEMBL4092975
7.72	IC50	19	nM	CHEMBL1231795
7.72	IC50	19	nM	CHEMBL4560792
7.72	IC50	19	nM	CHEMBL4435107
7.72	IC50	19	nM	CHEMBL4452780
7.70	IC50	20	nM	CHEMBL4068291
7.70	IC50	20	nM	CHEMBL4069640
7.70	IC50	20	nM	CHEMBL4063767
7.70	IC50	20	nM	CHEMBL569864
7.70	IC50	20	nM	CHEMBL576781

PubChem BioAssay actives

223 with measured affinity, of 517 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
6-[4-[4-[(1-benzylpiperidin-4-yl)amino]-6,7-dimethoxyquinazolin-2-yl]piperazin-1-yl]-N-hydroxyhexanamide	1888583: Inhibition of GLP (unknown origin)	ic50	0.0013	uM
6-[4-[6,7-dimethoxy-4-[(1-propan-2-ylpiperidin-4-yl)amino]quinazolin-2-yl]piperazin-1-yl]-N-hydroxyhexanamide	1888583: Inhibition of GLP (unknown origin)	ic50	0.0016	uM
2-cyclohexyl-6-methoxy-N-(1-propan-2-ylpiperidin-4-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-amine	2103448: Inhibition of GLP (unknown origin)	ic50	0.0025	uM
2-(4,4-difluoropiperidin-1-yl)-6-methoxy-N-(1-propan-2-ylpiperidin-4-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-amine	1947846: Inhibition of GLP (unknown origin)	ic50	0.0025	uM
2-N-cyclopentyl-6,7-dimethoxy-2-N-methyl-4-N-(1-methylpiperidin-4-yl)quinazoline-2,4-diamine	1487293: Inhibition of human GLP catalytic domain (951 to 1235 residues) expressed in Escherichia coli BL21 (DE3) using biotinylated H3 (1 to 25 residues) as substrate preincubated for 20 mins in presence of [3H]SAM measured after 2 hrs by scintillation proximity assay	ic50	0.0040	uM
6,7-dimethoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinazolin-4-amine	1438168: Inhibition of recombinant GLP catalytic SET domain (982 to 1266 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) codon plus RIL assessed as inhibition of methylation activity using biotin-labeled H3 (1 to 25 residues) as substrate and [3H]-SAM after 2 hrs by scintillation proximity assay	ic50	0.0040	uM
6,7-dimethoxy-2-N-methyl-4-N-(1-methylpiperidin-4-yl)-2-N-propylquinazoline-2,4-diamine	1487293: Inhibition of human GLP catalytic domain (951 to 1235 residues) expressed in Escherichia coli BL21 (DE3) using biotinylated H3 (1 to 25 residues) as substrate preincubated for 20 mins in presence of [3H]SAM measured after 2 hrs by scintillation proximity assay	ic50	0.0050	uM
N-[6-methoxy-4-[(1-methylpiperidin-4-yl)amino]-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-2-yl]-N-methylprop-2-enamide	1990873: Inhibition of GLP (unknown origin) by AlphaLISA assay	ic50	0.0050	uM
2-N-cyclohexyl-6,7-dimethoxy-2-N-methyl-4-N-(1-methylpiperidin-4-yl)quinazoline-2,4-diamine	1487293: Inhibition of human GLP catalytic domain (951 to 1235 residues) expressed in Escherichia coli BL21 (DE3) using biotinylated H3 (1 to 25 residues) as substrate preincubated for 20 mins in presence of [3H]SAM measured after 2 hrs by scintillation proximity assay	ic50	0.0060	uM
6,7-dimethoxy-N-(1-methylpiperidin-4-yl)-2-morpholin-4-ylquinolin-4-amine	1487293: Inhibition of human GLP catalytic domain (951 to 1235 residues) expressed in Escherichia coli BL21 (DE3) using biotinylated H3 (1 to 25 residues) as substrate preincubated for 20 mins in presence of [3H]SAM measured after 2 hrs by scintillation proximity assay	ic50	0.0060	uM
6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)-7-(3-pyrrolidin-1-ylprop-1-ynyl)quinazolin-4-amine	1552779: Inhibition of N-terminal GST tagged human recombinant EHMT1 (794 to 1294 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in conversion of SAH to AMP using histone H3 as substrate and SAH as cosubstrate incubated for 30 mins by AMP Glo detection assay	ic50	0.0060	uM
2-N-hexyl-6,7-dimethoxy-4-N-(1-methylpiperidin-4-yl)quinazoline-2,4-diamine	1438168: Inhibition of recombinant GLP catalytic SET domain (982 to 1266 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) codon plus RIL assessed as inhibition of methylation activity using biotin-labeled H3 (1 to 25 residues) as substrate and [3H]-SAM after 2 hrs by scintillation proximity assay	ic50	0.0070	uM
7-[3-(dimethylamino)propyl]-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinazolin-4-amine	1552779: Inhibition of N-terminal GST tagged human recombinant EHMT1 (794 to 1294 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in conversion of SAH to AMP using histone H3 as substrate and SAH as cosubstrate incubated for 30 mins by AMP Glo detection assay	ic50	0.0090	uM
6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)-7-(3-pyrrolidin-1-ylpropyl)quinazolin-4-amine	1552779: Inhibition of N-terminal GST tagged human recombinant EHMT1 (794 to 1294 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in conversion of SAH to AMP using histone H3 as substrate and SAH as cosubstrate incubated for 30 mins by AMP Glo detection assay	ic50	0.0090	uM
6-[[4-[(1-benzylpiperidin-4-yl)amino]-6,7-dimethoxyquinazolin-2-yl]amino]-N-hydroxyhexanamide	1888583: Inhibition of GLP (unknown origin)	ic50	0.0092	uM
2-N-hexyl-6,7-dimethoxy-4-N-(1-methylpiperidin-4-yl)quinoline-2,4-diamine	1487293: Inhibition of human GLP catalytic domain (951 to 1235 residues) expressed in Escherichia coli BL21 (DE3) using biotinylated H3 (1 to 25 residues) as substrate preincubated for 20 mins in presence of [3H]SAM measured after 2 hrs by scintillation proximity assay	ic50	0.0110	uM
6,7-dimethoxy-2-morpholin-4-yl-N-(1-propylpiperidin-4-yl)quinazolin-4-amine	1438168: Inhibition of recombinant GLP catalytic SET domain (982 to 1266 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) codon plus RIL assessed as inhibition of methylation activity using biotin-labeled H3 (1 to 25 residues) as substrate and [3H]-SAM after 2 hrs by scintillation proximity assay	ic50	0.0110	uM
7-[3-(dimethylamino)prop-1-ynyl]-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinazolin-4-amine	1552779: Inhibition of N-terminal GST tagged human recombinant EHMT1 (794 to 1294 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in conversion of SAH to AMP using histone H3 as substrate and SAH as cosubstrate incubated for 30 mins by AMP Glo detection assay	ic50	0.0110	uM
6-[[6,7-dimethoxy-4-[(1-methylpiperidin-4-yl)amino]quinazolin-2-yl]amino]-N-hydroxyhexanamide	1888583: Inhibition of GLP (unknown origin)	ic50	0.0110	uM
7-[[6,7-dimethoxy-4-[(1-propan-2-ylpiperidin-4-yl)amino]quinazolin-2-yl]amino]-N-hydroxyheptanamide	1888583: Inhibition of GLP (unknown origin)	ic50	0.0110	uM
6,7-dimethoxy-2-N,2-N-dimethyl-4-N-(1-methylpiperidin-4-yl)quinazoline-2,4-diamine	1487293: Inhibition of human GLP catalytic domain (951 to 1235 residues) expressed in Escherichia coli BL21 (DE3) using biotinylated H3 (1 to 25 residues) as substrate preincubated for 20 mins in presence of [3H]SAM measured after 2 hrs by scintillation proximity assay	ic50	0.0110	uM
5’-methoxy-6’-(3-pyrrolidin-1-ylpropoxy)spiro[cyclobutane-1,3’-indole]-2’-amine	1552779: Inhibition of N-terminal GST tagged human recombinant EHMT1 (794 to 1294 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in conversion of SAH to AMP using histone H3 as substrate and SAH as cosubstrate incubated for 30 mins by AMP Glo detection assay	ic50	0.0110	uM
6,7-dimethoxy-N-(1-methylpiperidin-4-yl)-2-pyrrolidin-1-ylquinazolin-4-amine	1438168: Inhibition of recombinant GLP catalytic SET domain (982 to 1266 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) codon plus RIL assessed as inhibition of methylation activity using biotin-labeled H3 (1 to 25 residues) as substrate and [3H]-SAM after 2 hrs by scintillation proximity assay	ic50	0.0120	uM
N-(1-cyclopropylpiperidin-4-yl)-6,7-dimethoxy-2-morpholin-4-ylquinazolin-4-amine	1438168: Inhibition of recombinant GLP catalytic SET domain (982 to 1266 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) codon plus RIL assessed as inhibition of methylation activity using biotin-labeled H3 (1 to 25 residues) as substrate and [3H]-SAM after 2 hrs by scintillation proximity assay	ic50	0.0120	uM
2-[3-[6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-4-[(1-methylpiperidin-4-yl)amino]quinazolin-7-yl]propyl-methylamino]ethanol	1552779: Inhibition of N-terminal GST tagged human recombinant EHMT1 (794 to 1294 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in conversion of SAH to AMP using histone H3 as substrate and SAH as cosubstrate incubated for 30 mins by AMP Glo detection assay	ic50	0.0120	uM
1-[3-[6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-4-[(1-methylpiperidin-4-yl)amino]quinazolin-7-yl]prop-2-ynyl]pyrrolidin-2-one	1552779: Inhibition of N-terminal GST tagged human recombinant EHMT1 (794 to 1294 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in conversion of SAH to AMP using histone H3 as substrate and SAH as cosubstrate incubated for 30 mins by AMP Glo detection assay	ic50	0.0120	uM
6,7-dimethoxy-N-(1-methylpiperidin-4-yl)-2-piperidin-1-ylquinazolin-4-amine	1438168: Inhibition of recombinant GLP catalytic SET domain (982 to 1266 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) codon plus RIL assessed as inhibition of methylation activity using biotin-labeled H3 (1 to 25 residues) as substrate and [3H]-SAM after 2 hrs by scintillation proximity assay	ic50	0.0120	uM
6,7-dimethoxy-N-(1-methylpiperidin-4-yl)-2-morpholin-4-ylquinazolin-4-amine	1438168: Inhibition of recombinant GLP catalytic SET domain (982 to 1266 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) codon plus RIL assessed as inhibition of methylation activity using biotin-labeled H3 (1 to 25 residues) as substrate and [3H]-SAM after 2 hrs by scintillation proximity assay	ic50	0.0130	uM
2-N-[4-(difluoromethoxy)-3-(2,3,4,7-tetrahydro-1H-azepin-5-yl)phenyl]-4-N,6-dimethylpyrimidine-2,4-diamine	1722380: Inhibition of GLP (unknown origin)	ic50	0.0147	uM
6,7-dimethoxy-2-morpholin-4-yl-N-(1-propan-2-ylpiperidin-4-yl)quinazolin-4-amine	1438168: Inhibition of recombinant GLP catalytic SET domain (982 to 1266 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) codon plus RIL assessed as inhibition of methylation activity using biotin-labeled H3 (1 to 25 residues) as substrate and [3H]-SAM after 2 hrs by scintillation proximity assay	ic50	0.0150	uM
7-[2-[2-(dimethylamino)ethoxy]ethoxy]-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinazolin-4-amine	497477: Activity at methyl transferase activity GLP by enzyme coupled S-adenocylehomocystein detection assay	ic50	0.0150	uM
N-(1-cyclohexylpiperidin-4-yl)-6-methoxy-7-(3-piperidin-1-ylpropoxy)-2-(4-propan-2-yl-1,4-diazepan-1-yl)quinazolin-4-amine	618482: Inhibition of GLP assessed as hydrolysis of S-adenosyl-L-homocysteine after 2 mins by SAHH-coupled fluorescence assay	ic50	0.0150	uM
2-(azepan-1-yl)-6,7-dimethoxy-N-(1-methylpiperidin-4-yl)quinazolin-4-amine	1438168: Inhibition of recombinant GLP catalytic SET domain (982 to 1266 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) codon plus RIL assessed as inhibition of methylation activity using biotin-labeled H3 (1 to 25 residues) as substrate and [3H]-SAM after 2 hrs by scintillation proximity assay	ic50	0.0160	uM
1-[3-[6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-4-[(1-methylpiperidin-4-yl)amino]quinazolin-7-yl]propyl]pyrrolidin-2-one	1552779: Inhibition of N-terminal GST tagged human recombinant EHMT1 (794 to 1294 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in conversion of SAH to AMP using histone H3 as substrate and SAH as cosubstrate incubated for 30 mins by AMP Glo detection assay	ic50	0.0160	uM
N-[6-methoxy-4-[(1-propan-2-ylpiperidin-4-yl)amino]-7-(3-pyrrolidin-1-ylpropoxy)quinolin-2-yl]propanamide	1874195: Binding affinity to human GLP (982 to 1266 residues) assessed as dissociation constant measured after 1 hr by isothermal titration calorimetry method	kd	0.0160	uM
2-N-cyclobutyl-6,7-dimethoxy-2-N-methyl-4-N-(1-methylpiperidin-4-yl)quinazoline-2,4-diamine	1487293: Inhibition of human GLP catalytic domain (951 to 1235 residues) expressed in Escherichia coli BL21 (DE3) using biotinylated H3 (1 to 25 residues) as substrate preincubated for 20 mins in presence of [3H]SAM measured after 2 hrs by scintillation proximity assay	ic50	0.0170	uM
6,7-dimethoxy-2-N-methyl-4-N-(1-methylpiperidin-4-yl)-2-N-propan-2-ylquinazoline-2,4-diamine	1487293: Inhibition of human GLP catalytic domain (951 to 1235 residues) expressed in Escherichia coli BL21 (DE3) using biotinylated H3 (1 to 25 residues) as substrate preincubated for 20 mins in presence of [3H]SAM measured after 2 hrs by scintillation proximity assay	ic50	0.0180	uM
2-N-hexyl-6,7-dimethoxy-2-N-methyl-4-N-(1-methylpiperidin-4-yl)quinazoline-2,4-diamine	1438168: Inhibition of recombinant GLP catalytic SET domain (982 to 1266 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) codon plus RIL assessed as inhibition of methylation activity using biotin-labeled H3 (1 to 25 residues) as substrate and [3H]-SAM after 2 hrs by scintillation proximity assay	ic50	0.0180	uM
2-N-ethyl-6,7-dimethoxy-2-N-methyl-4-N-(1-methylpiperidin-4-yl)quinazoline-2,4-diamine	1487293: Inhibition of human GLP catalytic domain (951 to 1235 residues) expressed in Escherichia coli BL21 (DE3) using biotinylated H3 (1 to 25 residues) as substrate preincubated for 20 mins in presence of [3H]SAM measured after 2 hrs by scintillation proximity assay	ic50	0.0180	uM
2-cyclohexyl-7-[3-(dimethylamino)prop-1-ynyl]-6-methoxy-N-(1-propan-2-ylpiperidin-4-yl)quinazolin-4-amine	1552779: Inhibition of N-terminal GST tagged human recombinant EHMT1 (794 to 1294 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in conversion of SAH to AMP using histone H3 as substrate and SAH as cosubstrate incubated for 30 mins by AMP Glo detection assay	ic50	0.0190	uM
6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)-7-(2-piperidin-2-ylethyl)quinazolin-4-amine	1552779: Inhibition of N-terminal GST tagged human recombinant EHMT1 (794 to 1294 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in conversion of SAH to AMP using histone H3 as substrate and SAH as cosubstrate incubated for 30 mins by AMP Glo detection assay	ic50	0.0190	uM
2-cyclohexyl-7-[3-(dimethylamino)propyl]-6-methoxy-N-(1-propan-2-ylpiperidin-4-yl)quinazolin-4-amine	1552779: Inhibition of N-terminal GST tagged human recombinant EHMT1 (794 to 1294 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in conversion of SAH to AMP using histone H3 as substrate and SAH as cosubstrate incubated for 30 mins by AMP Glo detection assay	ic50	0.0190	uM
2-N-(cyclohexylmethyl)-6,7-dimethoxy-2-N-methyl-4-N-(1-methylpiperidin-4-yl)quinazoline-2,4-diamine	1487293: Inhibition of human GLP catalytic domain (951 to 1235 residues) expressed in Escherichia coli BL21 (DE3) using biotinylated H3 (1 to 25 residues) as substrate preincubated for 20 mins in presence of [3H]SAM measured after 2 hrs by scintillation proximity assay	ic50	0.0200	uM
2-N-ethyl-6,7-dimethoxy-4-N-(1-methylpiperidin-4-yl)-2-N-propylquinazoline-2,4-diamine	1487293: Inhibition of human GLP catalytic domain (951 to 1235 residues) expressed in Escherichia coli BL21 (DE3) using biotinylated H3 (1 to 25 residues) as substrate preincubated for 20 mins in presence of [3H]SAM measured after 2 hrs by scintillation proximity assay	ic50	0.0200	uM
2-[[6,7-dimethoxy-4-[(1-methylpiperidin-4-yl)amino]quinazolin-2-yl]-methylamino]ethanol	1487293: Inhibition of human GLP catalytic domain (951 to 1235 residues) expressed in Escherichia coli BL21 (DE3) using biotinylated H3 (1 to 25 residues) as substrate preincubated for 20 mins in presence of [3H]SAM measured after 2 hrs by scintillation proximity assay	ic50	0.0200	uM
7-[3-(dimethylamino)propoxy]-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinazolin-4-amine	442060: Inhibition of GLP by Thioglo assay	ic50	0.0200	uM
7-[[6,7-dimethoxy-4-[(1-methylpiperidin-4-yl)amino]quinazolin-2-yl]amino]-N-hydroxyheptanamide	1888583: Inhibition of GLP (unknown origin)	ic50	0.0210	uM
2-N-butyl-2-N-ethyl-6,7-dimethoxy-4-N-(1-methylpiperidin-4-yl)quinazoline-2,4-diamine	1487293: Inhibition of human GLP catalytic domain (951 to 1235 residues) expressed in Escherichia coli BL21 (DE3) using biotinylated H3 (1 to 25 residues) as substrate preincubated for 20 mins in presence of [3H]SAM measured after 2 hrs by scintillation proximity assay	ic50	0.0230	uM
2-N,2-N-diethyl-6,7-dimethoxy-4-N-(1-methylpiperidin-4-yl)quinazoline-2,4-diamine	1487293: Inhibition of human GLP catalytic domain (951 to 1235 residues) expressed in Escherichia coli BL21 (DE3) using biotinylated H3 (1 to 25 residues) as substrate preincubated for 20 mins in presence of [3H]SAM measured after 2 hrs by scintillation proximity assay	ic50	0.0230	uM
2-N-[2-(dimethylamino)ethyl]-6,7-dimethoxy-2-N-methyl-4-N-(1-methylpiperidin-4-yl)quinazoline-2,4-diamine	1487293: Inhibition of human GLP catalytic domain (951 to 1235 residues) expressed in Escherichia coli BL21 (DE3) using biotinylated H3 (1 to 25 residues) as substrate preincubated for 20 mins in presence of [3H]SAM measured after 2 hrs by scintillation proximity assay	ic50	0.0240	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases reaction, increases expression, decreases expression, increases reaction	3
Benzo(a)pyrene	decreases expression	3
epigallocatechin gallate	decreases reaction, increases expression, affects cotreatment, decreases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, increases expression	2
Estradiol	affects expression, decreases expression, increases reaction	2
Valproic Acid	decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Particulate Matter	increases abundance, increases expression	2
UNC0642	decreases activity	1
TAK-243	decreases sumoylation	1
dicrotophos	increases expression	1
geldanamycin	increases expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
bisphenol A	decreases methylation	1
trichostatin A	decreases expression	1
arsenite	affects binding, decreases reaction	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	decreases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
cupric oxide	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
CGP 52608	affects binding, increases reaction	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	affects cotreatment, decreases expression	1
sepantronium	decreases expression, decreases reaction	1
bisphenol S	increases methylation	1
MK-8776	increases expression	1
Vorinostat	decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Amiodarone	increases expression	1
Vehicle Emissions	increases abundance, increases expression	1

ChEMBL screening assays

181 unique, capped per target: 180 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3390897	Binding	Inhibition of G9a/GLP in human MDA-MB-231 cells assessed as reduction of H3K9me2 level after 48 hrs by flow cytometric analysis	Development of second generation epigenetic agents — Medchemcomm
CHEMBL4416352	ADMET	Inhibition of human EHMT1 expressed in Escherichia coli assessed as reduction in methylated histone H3 full length using histone H3 full length as substrate in presence of [3H] SAM incubated for 120 mins by scintillation counting	High-Affinity Alkynyl Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT). — J Med Chem

Cellosaurus cell lines

10 cell lines: 8 cancer cell line, 1 induced pluripotent stem cell, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B8F6	Abcam HCT 116 EHMT1 KO	Cancer cell line	Male
CVCL_B8V6	Abcam MCF-7 EHMT1 KO	Cancer cell line	Female
CVCL_B9HE	Abcam A-549 EHMT1 KO	Cancer cell line	Male
CVCL_IJ19	BIOT-0708-EHMT1	Induced pluripotent stem cell	Female
CVCL_KV99	InCELL Hunter A549 GLP Methyltransferase	Cancer cell line	Male
CVCL_SL52	HAP1 EHMT1 (-) 1	Cancer cell line	Male
CVCL_SL53	HAP1 EHMT1 (-) 2	Cancer cell line	Male
CVCL_SL54	HAP1 EHMT1 (-) 3	Cancer cell line	Male
CVCL_SL55	HAP1 EHMT1 (-) 4	Cancer cell line	Male
CVCL_ZB42	WAe009-A-28	Embryonic stem cell	Female

Clinical trials (associated diseases)

300 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,
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
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