NSD3

Summary

NSD3 (nuclear receptor binding SET domain protein 3, HGNC:12767) is a protein-coding gene on chromosome 8p11.23, encoding Histone-lysine N-methyltransferase NSD3 (Q9BZ95). Histone methyltransferase.

This gene is related to the Wolf-Hirschhorn syndrome candidate-1 gene and encodes a protein with PWWP (proline-tryptophan-tryptophan-proline) domains. This protein methylates histone H3 at lysine residues 4 and 27, which represses gene transcription. Two alternatively spliced variants have been described.

Source: NCBI Gene 54904 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 164 total
• Druggable target: yes — 5 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• MANE Select transcript: NM_023034

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12767
Approved symbol	NSD3
Name	nuclear receptor binding SET domain protein 3
Location	8p11.23
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20353, WHISTLE, KMT3F
Ensembl gene	ENSG00000147548
Ensembl biotype	protein_coding
OMIM	607083
Entrez	54904

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 11 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000316985, ENST00000317025, ENST00000433384, ENST00000525081, ENST00000526050, ENST00000527502, ENST00000528304, ENST00000528627, ENST00000528828, ENST00000529223, ENST00000534155, ENST00000534539, ENST00000879303, ENST00000935238, ENST00000935239

RefSeq mRNA: 2 — MANE Select: NM_023034 NM_017778, NM_023034

CCDS: CCDS43729, CCDS6105

Canonical transcript exons

ENST00000317025 — 24 exons

Exon	Start	End
ENSE00001217180	38305248	38305445
ENSE00001217255	38279540	38279681
ENSE00001217285	38299444	38299590
ENSE00001217426	38269704	38275882
ENSE00001305899	38314647	38314773
ENSE00001359946	38281467	38281583
ENSE00001359947	38288487	38288756
ENSE00001359948	38289393	38289505
ENSE00001359954	38304587	38304757
ENSE00001359961	38315416	38315544
ENSE00001359963	38315912	38316042
ENSE00001418059	38290475	38290677
ENSE00001612883	38338536	38338607
ENSE00001614885	38326730	38326856
ENSE00001636142	38318895	38318940
ENSE00001676369	38321072	38321172
ENSE00001684166	38329378	38329893
ENSE00001724871	38331431	38331585
ENSE00001772787	38337305	38337467
ENSE00002262898	38347497	38348215
ENSE00003504335	38276296	38276500
ENSE00003592995	38295796	38295952
ENSE00003620826	38278306	38278412
ENSE00003850138	38381799	38382271

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 97.11.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.0397 / max 252.8718, expressed in 1787 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
92747	9.1771	1715
92746	1.7896	861
92751	1.6321	846
92749	0.7926	359
92748	0.4088	166
92750	0.2393	77

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pylorus	UBERON:0001166	97.11	gold quality
colonic epithelium	UBERON:0000397	96.76	gold quality
ganglionic eminence	UBERON:0004023	96.68	gold quality
cortical plate	UBERON:0005343	96.63	gold quality
cardia of stomach	UBERON:0001162	96.61	gold quality
ventricular zone	UBERON:0003053	95.88	gold quality
entorhinal cortex	UBERON:0002728	95.41	gold quality
caput epididymis	UBERON:0004358	95.31	gold quality
sural nerve	UBERON:0015488	95.27	gold quality
mammary duct	UBERON:0001765	95.19	gold quality
nipple	UBERON:0002030	95.19	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.18	gold quality
middle temporal gyrus	UBERON:0002771	95.13	gold quality
superficial temporal artery	UBERON:0001614	95.11	gold quality
postcentral gyrus	UBERON:0002581	94.99	gold quality
corpus callosum	UBERON:0002336	94.95	gold quality
tonsil	UBERON:0002372	94.84	gold quality
parietal lobe	UBERON:0001872	94.83	gold quality
bronchial epithelial cell	CL:0002328	94.70	gold quality
lateral globus pallidus	UBERON:0002476	94.60	gold quality
trabecular bone tissue	UBERON:0002483	94.44	gold quality
calcaneal tendon	UBERON:0003701	94.20	gold quality
inferior vagus X ganglion	UBERON:0005363	94.10	gold quality
cauda epididymis	UBERON:0004360	94.07	gold quality
substantia nigra pars reticulata	UBERON:0001966	94.05	gold quality
germinal epithelium of ovary	UBERON:0001304	93.98	gold quality
adrenal tissue	UBERON:0018303	93.93	gold quality
globus pallidus	UBERON:0001875	93.92	gold quality
corpus epididymis	UBERON:0004359	93.87	gold quality
medial globus pallidus	UBERON:0002477	93.83	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-10	yes	4.28
E-MTAB-7606	no	544.39
E-HCAD-5	no	12.79
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NSD2

miRNA regulators (miRDB)

38 targeting NSD3, 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-8485	100.00	77.57	4731
HSA-MIR-3646	100.00	73.56	5283
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-202-3P	99.84	71.41	1290
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-142-5P	99.48	70.92	2416
HSA-MIR-5590-3P	99.48	70.91	2429
HSA-MIR-1276	99.36	68.18	1642
HSA-MIR-145-3P	99.33	67.66	764
HSA-MIR-2116-5P	99.32	69.34	1273
HSA-MIR-7515	99.31	68.22	1795

Literature-anchored findings (GeneRIF, showing 25)

• NSD3L depletion increased the invasiveness of MDA-MB-231 breast cancer cells indicating that NSD3L normally restrain cellular metastatic potential. Together the presented data indicates that NSD3L is a candidate tumor suppressor. (PMID:20599755)
• Overexpression of WHSC1L1 gene is associated with breast cancer. (PMID:20940404)
• Functional studies with Brd4 indicate that the ET domain mediates pTEFb-independent transcriptional activation through a subset of these associated factors, including NSD3. (PMID:21555454)
• Data indicate that siRNA attenuated the expression levels of CCNG1 and NEK7, implying that WHSC1L1 appears to activate the expression of CCNG1 and NEK7 in cancer cells. (PMID:23011637)
• methyltransferase NSD3 has chromatin-binding motifs, PHD5-C5HCH, that are distinct from other NSD (nuclear receptor SET domain) family members in their histone H3 recognition (PMID:23269674)
• PPAPDC1B and WHSC1L1 played a major role in regulating the survival of breast cancer, pancreatic adenocarcinoma and small-cell lung cancer-derived cell lines. (PMID:24051013)
• The involvement of the NSD3 methyltransferase as a component of the NUT fusion protein oncogenic complex identifies a new potential therapeutic target. (PMID:24875858)
• The results describe the binding of NSD1, 2 and 3 catalytic domains (CD) on histone tails through recognition of histone-lysine and methylation properties. (PMID:25494638)
• Studies indicate that the NSD methyltransferases NSD1, NSD2/WHSC1/MMSET and NSD3/WHSC1L1 were overexpressed, amplified or somatically mutated in multiple types of cancer, suggesting their critical role in cancer. (PMID:25942451)
• Results demonstrate that the AML maintenance function of BRD4 requires its interaction with the short isoform of NSD3 lacking the methyltransferase domain. This protein is an adaptor that sustains leukemia by linking BRD4 to the CHD8 chromatin remodeler. (PMID:26626481)
• This study demonstrates that over-expression of WHSC1L1 is linked to over-expression of ER-alpha in SUM-44 breast cancer cells and in primary human breast cancers. (PMID:27005559)
• WHSC1L1 and H3K36me2 are enriched in the gene bodies of the cell cycle-related genes CDC6 and CDK2, implying that WHSC1L1 directly regulates the transcription of these gene (PMID:27285764)
• Results extend the in vitro results and show that targeted expression of NSD3 to the mammary gland of FVB mice is oncogenic, consistent with the hypothesis that NSD3 is an important driver oncogene in human breast cancer. (PMID:28484924)
• Studies showed that depletion of NSD3 in osteosarcoma cell lines inhibited cell proliferation and survival, and induced cell apoptosis. RNA sequence analysis of tumor cell lines with NSD3 deletion revealed that NSD3 functions as either a transcriptional activator or a repressor. These results suggest that NSD3 may function as an oncogenic driver in osteosarcoma. (PMID:28901481)
• The observation that certain metabolic pathways are differentially regulated by NSD3s and Pdp3 suggests that, despite the structural similarity between their PWWP domains, the two proteins act by unique mechanisms and may recruit different downstream signaling complexes. (PMID:30320908)
• NSD3S stabilizes MYC through hindering its interaction with FBXW7. (PMID:31638140)
• NSD3-Induced Methylation of H3K36 Activates NOTCH Signaling to Drive Breast Tumor Initiation and Metastatic Progression. (PMID:32967925)
• Molecular basis of nucleosomal H3K36 methylation by NSD methyltransferases. (PMID:33361816)
• Elevated NSD3 histone methylation activity drives squamous cell lung cancer. (PMID:33536620)
• A common binding motif in the ET domain of BRD3 forms polymorphic structural interfaces with host and viral proteins. (PMID:33592170)
• Targeting H3K36 methyltransferases NSDs: a promising strategy for tumor targeted therapy. (PMID:34083510)
• Histone and DNA binding ability studies of the NSD subfamily of PWWP domains. (PMID:34271259)
• Elevated expression of nuclear receptor-binding SET domain 3 promotes pancreatic cancer cell growth. (PMID:34615858)
• The role of NSD1, NSD2, and NSD3 histone methyltransferases in solid tumors. (PMID:35532818)
• Histones Methyltransferase NSD3 Inhibits Lung Adenocarcinoma Glycolysis Through Interacting with PPP1CB to Decrease STAT3 Signaling Pathway. (PMID:39119928)

Cross-species orthologs

16 orthologs

Organism	Symbol	Gene ID
danio_rerio	nsd3	ENSDARG00000062765
mus_musculus	Nsd3	ENSMUSG00000054823
rattus_norvegicus	Nsd3	ENSRNOG00000015621
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), SETBP1 (ENSG00000152217), SUV39H2 (ENSG00000152455), NSD1 (ENSG00000165671), KMT2D (ENSG00000167548), EHMT1 (ENSG00000181090), SETD2 (ENSG00000181555), EHMT2 (ENSG00000204371), KMT2B (ENSG00000272333)

Protein

Protein identifiers

Histone-lysine N-methyltransferase NSD3 — Q9BZ95 (reviewed: Q9BZ95)

Alternative names: Nuclear SET domain-containing protein 3, Protein whistle, WHSC1-like 1 isoform 9 with methyltransferase activity to lysine, Wolf-Hirschhorn syndrome candidate 1-like protein 1

All UniProt accessions (5): Q9BZ95, E9PKA2, E9PKL3, E9PQ95, H0YE68

UniProt curated annotations — full annotation on UniProt →

Function. Histone methyltransferase. Preferentially dimethylates ‘Lys-4’ and ‘Lys-27’ of histone H3 forming H3K4me2 and H3K27me2. H3 ‘Lys-4’ methylation represents a specific tag for epigenetic transcriptional activation, while ‘Lys-27’ is a mark for transcriptional repression.

Subunit / interactions. Interacts with BRD4. Interacts (via KIKL motif) with BRD3 (via NET domain).

Subcellular location. Nucleus. Chromosome.

Tissue specificity. Highly expressed in brain, heart and skeletal muscle. Expressed at lower level in liver and lung.

Disease relevance. Defects in NSD3 may be involved in non small cell lung carcinomas (NSCLC). Amplified or overexpressed in NSCLC. A chromosomal aberration involving NSD3 is found in childhood acute myeloid leukemia. Translocation t(8;11)(p11.2;p15) with NUP98.

Domain organisation. The KIKL motif recognizes and binds the NET domain of BRD3.

Similarity. Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. SET2 subfamily.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9BZ95-1	1	yes
Q9BZ95-2	2
Q9BZ95-3	3
Q9BZ95-4	4
Q9BZ95-5	5

RefSeq proteins (2): NP_060248, NP_075447* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000313	PWWP_dom	Domain
IPR001214	SET_dom	Domain
IPR001965	Znf_PHD	Domain
IPR003616	Post-SET_dom	Domain
IPR006560	AWS_dom	Domain
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR019786	Zinc_finger_PHD-type_CS	Conserved_site
IPR019787	Znf_PHD-finger	Domain
IPR041306	C5HCH	Domain
IPR046341	SET_dom_sf	Homologous_superfamily
IPR047451	PWWP_NSD3_rpt1	Domain
IPR047453	PWWP_NSD3_rpt2	Domain
IPR047456	PHD2_NSD3	Domain
IPR047458	PHD4_NSD3	Domain
IPR047461	SET_NSD3	Domain
IPR047527	PHD5_NSD3	Domain
IPR050777	SET2_Histone-Lys_MeTrsfase	Family
IPR055197	PHDvar_NSD	Domain
IPR055198	NSD_PHD	Domain
IPR059153	NSD_PHD-1st	Domain

Pfam: PF00855, PF00856, PF17907, PF17982, PF22908, PF23004, PF23011

Enzyme classification (BRENDA):

• EC 2.1.1.356 — [histone H3]-lysine27 N-trimethyltransferase (BRENDA: 12 organisms, 23 substrates, 3 inhibitors, 14 Km, 13 kcat entries)
• EC 2.1.1.370 — [histone H3]-lysine4 N-dimethyltransferase (BRENDA: 2 organisms, 6 substrates, 0 inhibitors, 0 Km, 0 kcat entries)
• EC 2.1.1.371 — [histone H3]-lysine27 N-dimethyltransferase (BRENDA: 2 organisms, 7 substrates, 0 inhibitors, 0 Km, 0 kcat entries)
• EC 2.1.1.372 — [histone H4]-lysine20 N-trimethyltransferase (BRENDA: 2 organisms, 4 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
(+/-)-2’,3’-DIBENZYL-S-ADENOSYL-L-METHIONINE	0.072–0.917	3
(+/-)-3’-BENZYL-S-ADENOSYL-L-METHIONINE	0.086–2.8	3
HISTONE H3(K27)	0.2762–3.9	3
S-ADENOSYL-L-METHIONINE	0.06–0.126	3
(+/-)-2’-BENZYL-S-ADENOSYL-L-METHIONINE	0.086–0.128	2

Catalyzed reactions (Rhea), 2 shown:

• L-lysyl(4)-[histone H3] + 2 S-adenosyl-L-methionine = N(6),N(6)-dimethyl-L-lysyl(4)-[histone H3] + 2 S-adenosyl-L-homocysteine + 2 H(+) (RHEA:64448)
• L-lysyl(27)-[histone H3] + 2 S-adenosyl-L-methionine = N(6),N(6)-dimethyl-L-lysyl(27)-[histone H3] + 2 S-adenosyl-L-homocysteine + 2 H(+) (RHEA:64452)

UniProt features (115 total): strand 35, helix 18, turn 11, compositionally biased region 7, modified residue 7, cross-link 7, sequence conflict 6, domain 5, region of interest 5, splice variant 5, zinc finger region 4, sequence variant 2, chain 1, coiled-coil region 1, short sequence motif 1

Structure

Experimental structures (PDB)

25 structures.

PDB	Method	Resolution (Å)
6G25	X-RAY DIFFRACTION	1.43
4GNE	X-RAY DIFFRACTION	1.47
4GNF	X-RAY DIFFRACTION	1.55
6CEN	X-RAY DIFFRACTION	1.61
6G2B	X-RAY DIFFRACTION	1.61
6G27	X-RAY DIFFRACTION	1.65
6G29	X-RAY DIFFRACTION	1.7
4GNG	X-RAY DIFFRACTION	1.73
6G2F	X-RAY DIFFRACTION	1.74
6G2C	X-RAY DIFFRACTION	1.76
5UPD	X-RAY DIFFRACTION	1.8
6G2O	X-RAY DIFFRACTION	1.81
6G2E	X-RAY DIFFRACTION	1.85
4RXJ	X-RAY DIFFRACTION	2.1
6G24	X-RAY DIFFRACTION	2.1
4GND	X-RAY DIFFRACTION	2.27
6G3T	X-RAY DIFFRACTION	2.53
6G3P	X-RAY DIFFRACTION	2.8
7CRQ	ELECTRON MICROSCOPY	3.15
7CRP	ELECTRON MICROSCOPY	3.2
7CRR	ELECTRON MICROSCOPY	3.48
2DAQ	SOLUTION NMR
2NCZ	SOLUTION NMR
2ND1	SOLUTION NMR
7JYN	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BZ95-F1	62.29	0.22

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 (14): 150, 457, 585, 587, 590, 655, 790, 218, 245, 413, 502, 532, 628, 1151

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-3214841	PKMTs methylate histone lysines

MSigDB gene sets: 253 (showing top): E2F_Q4, E2F_Q4_01, ATACCTC_MIR202, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, FOXO1_01, CACCAGC_MIR138, GGAMTNNNNNTCCY_UNKNOWN, GGCNKCCATNK_UNKNOWN, CEBPB_01, E2F_Q3, AAACCAC_MIR140, FREAC3_01, WANG_LMO4_TARGETS_DN, FOSTER_TOLERANT_MACROPHAGE_UP, AML_Q6

GO Biological Process (5): regulation of DNA-templated transcription (GO:0006355), methylation (GO:0032259), positive regulation of DNA-templated transcription (GO:0045893), chromatin organization (GO:0006325), chromatin remodeling (GO:0006338)

GO Molecular Function (14): zinc ion binding (GO:0008270), histone H3K36 methyltransferase activity (GO:0046975), transcription regulator activator activity (GO:0140537), histone H3 methyltransferase activity (GO:0140938), histone H3K4 dimethyltransferase activity (GO:0140946), histone H3K27 trimethyltransferase activity (GO:0140951), histone H3K27 dimethyltransferase activity (GO:0140952), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740), histone methyltransferase activity (GO:0042054), histone H3K4 methyltransferase activity (GO:0042800), metal ion binding (GO:0046872), histone H3K27 methyltransferase activity (GO:0046976)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Chromatin modifying enzymes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein-lysine N-methyltransferase activity	3
histone H3 methyltransferase activity	3
DNA-templated transcription	2
regulation of gene expression	2
histone H3K27 methyltransferase activity	2
cellular anatomical structure	2
regulation of RNA biosynthetic process	1
metabolic process	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
cellular component organization	1
chromatin organization	1
transition metal ion binding	1
transcription regulator activity	1
molecular function activator activity	1
histone methyltransferase activity	1
histone H3K4 methyltransferase activity	1
binding	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
protein methyltransferase activity	1
histone modifying activity	1
cation binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1780 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NSD3	BRD4	O60885	983
NSD3	NUP98	P52948	824
NSD3	Q08EI0	Q08EI0	819
NSD3	NUTM1	Q86Y26	810
NSD3	BRD2	P25440	800
NSD3	ZNF532	Q9HCE3	769
NSD3	JMJD6	Q6NYC1	743
NSD3	EHMT2	Q96KQ7	696
NSD3	BRD3	Q15059	679
NSD3	PSIP1	O75475	679
NSD3	H3-3A	P06351	673
NSD3	H3C1	P02295	673
NSD3	H3-5	Q6NXT2	672
NSD3	H3-4	Q16695	671
NSD3	H3-7	Q5TEC6	671
NSD3	H3C14	Q71DI3	671

IntAct

90 interactions, top by confidence:

A	B	Type	Score
CBX5	NSD3	psi-mi:“MI:0915”(physical association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
MLLT6	NSD3	psi-mi:“MI:0915”(physical association)	0.560
NSD3	HEL25	psi-mi:“MI:0915”(physical association)	0.560
NSD3	MLLT6	psi-mi:“MI:0915”(physical association)	0.560
HEL25	NSD3	psi-mi:“MI:0915”(physical association)	0.560
ESR1	NSD3	psi-mi:“MI:0915”(physical association)	0.550
RAD51	NSD3	psi-mi:“MI:0915”(physical association)	0.540
NSD3	RAD51	psi-mi:“MI:0915”(physical association)	0.540
NSD3	RAD51	psi-mi:“MI:0403”(colocalization)	0.540
NSD3	ATM	psi-mi:“MI:0915”(physical association)	0.510
NSD3	DAXX	psi-mi:“MI:0915”(physical association)	0.510
NSD3	HOXC4	psi-mi:“MI:0915”(physical association)	0.510
MNDA	NSD3	psi-mi:“MI:0915”(physical association)	0.510
SLU7	NSD3	psi-mi:“MI:0915”(physical association)	0.510
ATM	NSD3	psi-mi:“MI:0915”(physical association)	0.510
NSD3	EPB41	psi-mi:“MI:0915”(physical association)	0.400
NSD3	RPL30	psi-mi:“MI:0915”(physical association)	0.400
NSD3	rs4x_rs4y1_rs4y2_human	psi-mi:“MI:0915”(physical association)	0.400
DOCK7	NSD3	psi-mi:“MI:0915”(physical association)	0.370
ETV3	NSD3	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (165): WHSC1L1 (Two-hybrid), WHSC1L1 (Two-hybrid), BRD4 (Affinity Capture-Western), WHSC1L1 (Affinity Capture-Western), WHSC1L1 (Two-hybrid), WHSC1L1 (Two-hybrid), WHSC1L1 (Two-hybrid), WHSC1L1 (Two-hybrid), WHSC1L1 (Two-hybrid), WHSC1L1 (Two-hybrid), WHSC1L1 (Two-hybrid), WHSC1L1 (Two-hybrid), WHSC1L1 (Two-hybrid), WHSC1L1 (Two-hybrid), WHSC1L1 (Two-hybrid)

ESM2 similar proteins: A0A286Y9D1, A0JMK9, A2BIL7, A8DZJ1, B2KF05, B2RRD7, B4KLY7, F4IDY7, O15042, O94880, O97159, P55201, P97496, Q05913, Q20448, Q2T9V9, Q3T095, Q4V7A6, Q5EA28, Q5R7X2, Q61103, Q63ZP1, Q6DD45, Q6FSB1, Q6GQJ2, Q6IE81, Q6IE82, Q6NV83, Q6NWE1, Q6P2L6, Q6ZPI0, Q7KRW8, Q7ZVP1, Q803A0, Q8BRB7, Q8WML3, Q8WUB8, Q92613, Q92785, Q92922

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

3 interactions.

A	Effect	B	Mechanism
NSD3	“up-regulates activity”	IRF3	methylation
NSD3	“up-regulates quantity by stabilization”	MYC	binding
NSD3	“up-regulates activity”	MYC	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 77 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
Regulation of TP53 Degradation	5	27.1×	2e-04
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	5	13.6×	3e-03
G2/M DNA damage checkpoint	5	11.1×	5e-03
Transcriptional Regulation by TP53	6	6.9×	8e-03
Dengue Virus-Host Interactions	7	5.9×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
nucleosome assembly	6	11.7×	5e-03
chromatin remodeling	8	8.1×	5e-03
DNA damage response	8	5.9×	7e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — LUSC.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	120
Likely benign	10
Benign	7

Top pathogenic / likely-pathogenic (0)

SpliceAI

4622 predictions. Top by Δscore:

Variant	Effect	Δscore
8:38276496:GCCGA:G	acceptor_gain	1.0000
8:38276497:CCGA:C	acceptor_gain	1.0000
8:38276497:CCGAC:C	acceptor_gain	1.0000
8:38276498:CGA:C	acceptor_gain	1.0000
8:38276498:CGAC:C	acceptor_gain	1.0000
8:38276499:G:T	acceptor_gain	1.0000
8:38276501:C:CC	acceptor_gain	1.0000
8:38276502:T:G	acceptor_loss	1.0000
8:38276505:C:CT	acceptor_gain	1.0000
8:38276506:A:T	acceptor_gain	1.0000
8:38279535:TTTA:T	donor_loss	1.0000
8:38279536:TTA:T	donor_loss	1.0000
8:38279537:TACCT:T	donor_loss	1.0000
8:38279538:ACCT:A	donor_loss	1.0000
8:38279550:A:AC	donor_gain	1.0000
8:38279677:CGGTC:C	acceptor_gain	1.0000
8:38279680:TC:T	acceptor_gain	1.0000
8:38279681:CC:C	acceptor_gain	1.0000
8:38279682:C:CC	acceptor_gain	1.0000
8:38279685:C:CT	acceptor_gain	1.0000
8:38279686:A:T	acceptor_gain	1.0000
8:38281499:CA:C	donor_gain	1.0000
8:38281580:CACC:C	acceptor_gain	1.0000
8:38281582:CC:C	acceptor_gain	1.0000
8:38281582:CCCTG:C	acceptor_loss	1.0000
8:38281583:CC:C	acceptor_gain	1.0000
8:38281584:C:A	acceptor_loss	1.0000
8:38281585:T:A	acceptor_loss	1.0000
8:38289386:GACTT:G	donor_loss	1.0000
8:38289387:ACTT:A	donor_loss	1.0000

AlphaMissense

9491 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:38278333:G:C	C1280W	1.000
8:38278335:A:G	C1280R	1.000
8:38278350:A:G	C1275R	1.000
8:38278356:A:G	C1273R	1.000
8:38279595:C:A	W1235C	1.000
8:38279595:C:G	W1235C	1.000
8:38279597:A:G	W1235R	1.000
8:38279597:A:T	W1235R	1.000
8:38279610:A:C	C1230W	1.000
8:38279612:A:G	C1230R	1.000
8:38279624:A:G	C1226R	1.000
8:38279677:C:G	R1208P	1.000
8:38281559:C:G	G1176R	1.000
8:38288586:A:C	C1134W	1.000
8:38288588:A:G	C1134R	1.000
8:38288604:G:C	C1128W	1.000
8:38288605:C:T	C1128Y	1.000
8:38288606:A:G	C1128R	1.000
8:38288619:G:C	C1123W	1.000
8:38288621:A:G	C1123R	1.000
8:38288646:G:C	C1114W	1.000
8:38288648:A:G	C1114R	1.000
8:38288666:A:G	C1108R	1.000
8:38288690:A:G	C1100R	1.000
8:38288695:C:G	C1098S	1.000
8:38288696:A:G	C1098R	1.000
8:38288696:A:T	C1098S	1.000
8:38290669:G:T	P975Q	1.000
8:38290671:C:A	W974C	1.000
8:38290671:C:G	W974C	1.000

dbSNP variants (sampled 300 via entrez): RS1000034580 (8:38343046 A>T), RS1000048988 (8:38350840 T>A,C), RS1000058844 (8:38270782 A>G), RS1000085530 (8:38350543 T>C), RS1000102310 (8:38312111 G>A), RS1000139731 (8:38350332 C>A,G,T), RS1000268158 (8:38333654 T>G), RS1000275234 (8:38305012 C>T), RS1000279308 (8:38328078 G>A), RS1000327848 (8:38346895 T>A), RS1000330853 (8:38377618 G>A,T), RS1000366334 (8:38270423 A>C), RS1000380017 (8:38377284 C>T), RS1000431558 (8:38270684 A>C,T), RS1000458125 (8:38368329 A>G)

Disease associations

OMIM: gene MIM:607083 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): nut midline carcinoma (MONDO:0005563)

Orphanet (1): NUT midline carcinoma (Orphanet:443167)

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001301_2	Schizophrenia	1.000000e-10
GCST003469_12	Response to cognitive-behavioural therapy in anxiety disorder	4.000000e-06
GCST004521_242	Autism spectrum disorder or schizophrenia	4.000000e-09
GCST004946_16	Schizophrenia	1.000000e-11
GCST006624_111	Systolic blood pressure	1.000000e-20
GCST006803_65	Schizophrenia	6.000000e-10
GCST007267_45	Systolic blood pressure	3.000000e-14
GCST008103_171	Bipolar disorder	7.000000e-06
GCST90002404_314	Red cell distribution width	2.000000e-23

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007820	cognitive behavioural therapy
EFO:0006335	systolic blood pressure
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL3108646 (SINGLE PROTEIN), CHEMBL5465523 (PROTEIN-PROTEIN INTERACTION), CHEMBL6066035 (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: 49,999 (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
CHEMBL3137309	VENETOCLAX	4	9,389
CHEMBL265502	SURAMIN	3	36,848
CHEMBL1214186	SINEFUNGIN	2	2,165
CHEMBL1232461	MOLIBRESIB	2	1,538
CHEMBL1215331	PF-03882845	1	59

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

ChEMBL bioactivities

66 potent at pChembl≥5 of 93 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	CHEMBL5438312
9.00	IC50	1	nM	CHEMBL5408212
9.00	IC50	1	nM	CHEMBL5396709
9.00	IC50	1	nM	CHEMBL5419719
9.00	IC50	1	nM	CHEMBL5432302
9.00	IC50	1	nM	CHEMBL5425629
9.00	IC50	1	nM	CHEMBL5433029
7.52	Kd	30	nM	MOLIBRESIB
7.34	Kd	46	nM	CHEMBL5416709
7.04	Kd	91	nM	CHEMBL4758943
7.00	IC50	100	nM	MOLIBRESIB
6.96	IC50	110	nM	CHEMBL5186268
6.90	Kd	125.9	nM	CHEMBL4778517
6.78	Kd	166	nM	CHEMBL4778517
6.78	Kd	166	nM	CHEMBL5303349
6.77	Kd	170	nM	CHEMBL4778517
6.70	IC50	200	nM	CHEMBL4778517
6.69	IC50	203	nM	CHEMBL5277519
6.69	IC50	203	nM	CHEMBL5265919
6.58	IC50	260	nM	CHEMBL337173
6.47	IC50	340	nM	CHEMBL337173
6.39	IC50	410	nM	CHEMBL5558815
6.35	Kd	445	nM	CHEMBL4778517
6.35	Kd	445	nM	CHEMBL5303349
6.16	IC50	700	nM	CHEMBL6170408
6.12	IC50	750	nM	CHEMBL5422549
6.10	IC50	800	nM	CHEMBL5564764
6.08	IC50	840	nM	CHEMBL5542461
6.05	IC50	900	nM	CHEMBL337173
6.03	EC50	940	nM	CHEMBL5438548
5.96	IC50	1090	nM	CHEMBL5560302
5.89	Kd	1300	nM	CHEMBL5413676
5.89	IC50	1300	nM	VENETOCLAX
5.89	Kd	1300	nM	CHEMBL5424173
5.84	EC50	1430	nM	CHEMBL5438548
5.77	Kd	1700	nM	CHEMBL4778517
5.72	IC50	1900	nM	CHEMBL5427539
5.65	IC50	2230	nM	CHEMBL5564607
5.64	IC50	2300	nM	CHEMBL2058156
5.59	IC50	2560	nM	CHEMBL5557059
5.55	IC50	2800	nM	CHEMBL5560651
5.54	IC50	2910	nM	CHEMBL5567841
5.50	IC50	3200	nM	CHEMBL5402803
5.50	IC50	3200	nM	CHEMBL5414580
5.50	IC50	3200	nM	PF-03882845
5.50	IC50	3200	nM	CHAETOCIN
5.43	IC50	3740	nM	CHEMBL5559774
5.31	EC50	4900	nM	CHEMBL5413676
5.31	EC50	4900	nM	CHEMBL5424173
5.31	IC50	4930	nM	CHEMBL5567265

PubChem BioAssay actives

57 with measured affinity, of 245 total; 38 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
(1R)-1-[(3R)-3-amino-1-[4-[(6-aminopurin-9-yl)methyl]-6-(2,5-difluoro-4-methoxyphenyl)-3-pyridinyl]piperidin-3-yl]-2,2-difluoroethanol	2011300: Inhibition of NSD3 degradation in human KMS-11 cells assessed as reduction in H3K36me2 levels by FRET assay	ic50	0.0010	uM
9-[[5-[(3R)-3-amino-3-(cyclopropyloxymethyl)piperidin-1-yl]-2-(3,4-difluorophenyl)-4-pyridinyl]methyl]purin-6-amine	2011300: Inhibition of NSD3 degradation in human KMS-11 cells assessed as reduction in H3K36me2 levels by FRET assay	ic50	0.0010	uM
(1R)-1-[(3R)-3-amino-1-[4-[(6-aminopurin-9-yl)methyl]-6-(2,4,5-trifluorophenyl)-3-pyridinyl]piperidin-3-yl]-2,2-difluoroethanol	2011300: Inhibition of NSD3 degradation in human KMS-11 cells assessed as reduction in H3K36me2 levels by FRET assay	ic50	0.0010	uM
9-[[5-[(3R)-3-amino-3-(methoxymethyl)piperidin-1-yl]-2-(2,4-difluorophenyl)-4-pyridinyl]methyl]purin-6-amine	2011300: Inhibition of NSD3 degradation in human KMS-11 cells assessed as reduction in H3K36me2 levels by FRET assay	ic50	0.0010	uM
9-[[5-[(3R)-3-amino-3-(cyclobutyloxymethyl)piperidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-4-pyridinyl]methyl]purin-6-amine	2011300: Inhibition of NSD3 degradation in human KMS-11 cells assessed as reduction in H3K36me2 levels by FRET assay	ic50	0.0010	uM
9-[[5-[(3R)-3-amino-3-(methoxymethyl)piperidin-1-yl]-2-(3,4-difluorophenyl)-4-pyridinyl]methyl]purin-6-amine	2011300: Inhibition of NSD3 degradation in human KMS-11 cells assessed as reduction in H3K36me2 levels by FRET assay	ic50	0.0010	uM
9-[[5-[(3R)-3-amino-3-(methoxymethyl)piperidin-1-yl]-2-(5-chloro-2-fluorophenyl)-4-pyridinyl]methyl]purin-6-amine	2011300: Inhibition of NSD3 degradation in human KMS-11 cells assessed as reduction in H3K36me2 levels by FRET assay	ic50	0.0010	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2179168: Binding affinity against WHSC1L1 (unknown origin) assessed as apparent dissociation constant incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	kd	0.0300	uM
N-[[4-[[4-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenyl]carbamoyl]phenyl]methyl]-N-cyclopropyl-3-oxo-4H-1,4-benzoxazine-7-carboxamide	2011313: Binding affinity to human recombinant NSD3 PWWP1 domain assessed as dissociation constant	kd	0.0460	uM
4-cyano-N-cyclopropyl-N-(thiophen-2-ylmethyl)benzamide	1869404: Binding affinity to NSD3 (unknown origin) assessed as dissociation constant	kd	0.0910	uM
4-[5-[4-[(4-aminopiperidin-1-yl)methyl]-2,6-dimethylphenyl]-3-methylimidazol-4-yl]naphthalene-1-carbonitrile	2011306: Antagonist activity against recombinant human GST-tagged NSD3 PWWP1 domain (247 to 398 residues) expressed in Escherichia coli BL21(DE3) incubated for 60 mins by TR-FRET assay	ic50	0.1100	uM
[4-[5-(7-fluoroquinolin-4-yl)-1-methylimidazol-4-yl]-3,5-dimethylphenyl]methanamine	2072128: Binding affinity to human NSD3 PWWP1 domain (263 to 398 residues) expressed in Escherichia coli Bl21 (DE3) gold cells assessed as dissociation constant measured upto 180 secs by SPR analysis	kd	0.1259	uM
[3,5-dimethyl-4-[1-methyl-5-(7-methylquinolin-4-yl)imidazol-4-yl]phenyl]methanamine	1929281: Antagonist activity against recombinant human GST-tagged NSD3 PWWP1 domain (247 to 398 residues) incubated for 60 mins by TR-FRET assay	ic50	0.2030	uM
4-(3-methyl-5-phenylimidazol-4-yl)pyridine	2115832: Inhibition of GST-tagged NSD3 (247 to 398 residues) (unknown origin) incubated for 60 mins by TR-FRET assay	ic50	0.2030	uM
6-chloro-7-(2-morpholin-4-ylethylamino)quinoline-5,8-dione	2017800: Inhibition of N-terminal GST-fused recombinant human NSD3 (1021 to 1322 residues) expressed in Escherichia coli using SAM as substrate preincubated for 20 mins followed by substrate addition measured after 1 hrs by hotspot assay	ic50	0.2600	uM
9-[2-(4-bromo-3-fluorophenoxy)ethyl]purin-6-amine	2074541: Inhibition of recombinant NSD3 (1021 to 1322 residues) (unknown origin) expressed in Escherichia coli Rossetta (DE3) using H3K36me1 as substrate incubated for 20 mins in presence of SAM by HTRF assay	ic50	0.4100	uM
N-[3-[(7-chloro-5,8-dioxoquinolin-6-yl)amino]-1-bicyclo[1.1.1]pentanyl]but-2-ynamide	1966593: Inhibition of NSD3 (unknown origin)	ic50	0.7500	uM
4-[2-(6-aminopurin-9-yl)ethoxy]benzonitrile	2074541: Inhibition of recombinant NSD3 (1021 to 1322 residues) (unknown origin) expressed in Escherichia coli Rossetta (DE3) using H3K36me1 as substrate incubated for 20 mins in presence of SAM by HTRF assay	ic50	0.8000	uM
9-[2-(4-bromophenoxy)ethyl]purin-6-amine	2074541: Inhibition of recombinant NSD3 (1021 to 1322 residues) (unknown origin) expressed in Escherichia coli Rossetta (DE3) using H3K36me1 as substrate incubated for 20 mins in presence of SAM by HTRF assay	ic50	0.8400	uM
(2S,4R)-1-[(2S)-2-[11-[[4-[5-(7-fluoroquinolin-4-yl)-1-methylimidazol-4-yl]-3,5-dimethylphenyl]methylamino]undecanoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide	1985979: Induction of NSD3 degradation in human A549 cells measured after 72 hrs by Western blot analysis	ec50	0.9400	uM
9-[2-(4-chlorophenoxy)ethyl]purin-6-amine	2074541: Inhibition of recombinant NSD3 (1021 to 1322 residues) (unknown origin) expressed in Escherichia coli Rossetta (DE3) using H3K36me1 as substrate incubated for 20 mins in presence of SAM by HTRF assay	ic50	1.0900	uM
(2S,4R)-1-[(2S)-2-[9-[4-[[4-[5-(7-fluoroquinolin-4-yl)-1-methylimidazol-4-yl]-3,5-dimethylphenyl]methylamino]butanoylamino]nonanoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide	2011313: Binding affinity to human recombinant NSD3 PWWP1 domain assessed as dissociation constant	kd	1.3000	uM
(2R,4S)-1-[(2S)-2-[9-[4-[[4-[5-(7-fluoroquinolin-4-yl)-1-methylimidazol-4-yl]-3,5-dimethylphenyl]methylamino]butanoylamino]nonanoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1R)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide	2017807: Binding affinity to human NSD3 PPWP1 domain (247 to 402 residues) expressed in Escherichia coli assessed as dissociation constant	kd	1.3000	uM
Venetoclax	2017800: Inhibition of N-terminal GST-fused recombinant human NSD3 (1021 to 1322 residues) expressed in Escherichia coli using SAM as substrate preincubated for 20 mins followed by substrate addition measured after 1 hrs by hotspot assay	ic50	1.3000	uM
4-[5-(7-fluoroquinolin-4-yl)-1-methylimidazol-4-yl]-3,5-dimethyl-1,2-oxazole	2017802: Inhibition of NSD3 PWWP1 domain (unknown origin) by TR-FRET assay	ic50	1.9000	uM
5-[2-(6-aminopurin-9-yl)ethoxy]pyridine-2-carbonitrile	2074541: Inhibition of recombinant NSD3 (1021 to 1322 residues) (unknown origin) expressed in Escherichia coli Rossetta (DE3) using H3K36me1 as substrate incubated for 20 mins in presence of SAM by HTRF assay	ic50	2.2300	uM
5-(3-chloro-4-cyclohexylphenyl)-1-(3-methoxyphenyl)pyrazole-3-carboxylic acid	2017800: Inhibition of N-terminal GST-fused recombinant human NSD3 (1021 to 1322 residues) expressed in Escherichia coli using SAM as substrate preincubated for 20 mins followed by substrate addition measured after 1 hrs by hotspot assay	ic50	2.3000	uM
4-[2-(6-amino-8-oxo-7H-purin-9-yl)ethoxy]benzonitrile	2074541: Inhibition of recombinant NSD3 (1021 to 1322 residues) (unknown origin) expressed in Escherichia coli Rossetta (DE3) using H3K36me1 as substrate incubated for 20 mins in presence of SAM by HTRF assay	ic50	2.5600	uM
4-[2-(6-aminopurin-9-yl)ethoxy]-2-chlorobenzonitrile	2074541: Inhibition of recombinant NSD3 (1021 to 1322 residues) (unknown origin) expressed in Escherichia coli Rossetta (DE3) using H3K36me1 as substrate incubated for 20 mins in presence of SAM by HTRF assay	ic50	2.8000	uM
4-[2-(6-amino-8-sulfanylidene-7H-purin-9-yl)ethoxy]benzonitrile	2074541: Inhibition of recombinant NSD3 (1021 to 1322 residues) (unknown origin) expressed in Escherichia coli Rossetta (DE3) using H3K36me1 as substrate incubated for 20 mins in presence of SAM by HTRF assay	ic50	2.9100	uM
(1S,3R,11R,14S)-14-(hydroxymethyl)-3-[(1S,3R,11R,14S)-14-(hydroxymethyl)-18-methyl-13,17-dioxo-15,16-dithia-10,12,18-triazapentacyclo[12.2.2.01,12.03,11.04,9]octadeca-4,6,8-trien-3-yl]-18-methyl-15,16-dithia-10,12,18-triazapentacyclo[12.2.2.01,12.03,11.04,9]octadeca-4,6,8-triene-13,17-dione	2017800: Inhibition of N-terminal GST-fused recombinant human NSD3 (1021 to 1322 residues) expressed in Escherichia coli using SAM as substrate preincubated for 20 mins followed by substrate addition measured after 1 hrs by hotspot assay	ic50	3.2000	uM
(2S)-2-[[(2S)-2-[(2-acetamidoacetyl)amino]-3-methylbutanoyl]amino]-N-[(2S)-1-[[(2S,3S)-1-amino-3-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]hexanamide	2011288: Inhibition of NSD3 (unknown origin)	ic50	3.2000	uM
(2S,3S)-2-[[(2S)-2-[(2-acetamidoacetyl)amino]-3-methylbutanoyl]amino]-N-[(2S)-1-[[(2S,3S)-1-amino-3-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-3-methylhexanamide	2017796: Inhibition of N-terminal His-TEV-tagged human NSD3 (1054 to 1285 residues ) expressed in Escherichia coli using 3[H] SAM as substrate measured after 30 mins by biochemical assay	ic50	3.2000	uM
(3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydrobenzo[g]indazole-7-carboxylic acid	2017800: Inhibition of N-terminal GST-fused recombinant human NSD3 (1021 to 1322 residues) expressed in Escherichia coli using SAM as substrate preincubated for 20 mins followed by substrate addition measured after 1 hrs by hotspot assay	ic50	3.2000	uM
4-[2-(6-aminopurin-9-yl)ethoxy]benzene-1,2-dicarbonitrile	2074541: Inhibition of recombinant NSD3 (1021 to 1322 residues) (unknown origin) expressed in Escherichia coli Rossetta (DE3) using H3K36me1 as substrate incubated for 20 mins in presence of SAM by HTRF assay	ic50	3.7400	uM
9-[2-[4-(trifluoromethyl)phenoxy]ethyl]purin-6-amine	2074541: Inhibition of recombinant NSD3 (1021 to 1322 residues) (unknown origin) expressed in Escherichia coli Rossetta (DE3) using H3K36me1 as substrate incubated for 20 mins in presence of SAM by HTRF assay	ic50	4.9300	uM
[3,5-dimethyl-4-(1-methyl-5-pyridin-4-ylimidazol-4-yl)phenyl]methanamine	2017802: Inhibition of NSD3 PWWP1 domain (unknown origin) by TR-FRET assay	ic50	5.2000	uM
9-[2-(4-bromo-2-fluorophenoxy)ethyl]purin-6-amine	2074541: Inhibition of recombinant NSD3 (1021 to 1322 residues) (unknown origin) expressed in Escherichia coli Rossetta (DE3) using H3K36me1 as substrate incubated for 20 mins in presence of SAM by HTRF assay	ic50	6.7500	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression, increases expression	2
Acetaminophen	decreases expression, increases expression	2
Benzo(a)pyrene	increases mutagenesis, affects methylation	2
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression, affects cotreatment	1
TAK-243	affects sumoylation	1
bisphenol A	affects methylation	1
potassium perchlorate	increases expression	1
methylparaben	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
coumarin	decreases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
pentabromodiphenyl ether	increases expression	1
corosolic acid	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	decreases expression	1
Arsenic	affects methylation	1
Dexamethasone	affects cotreatment, increases expression	1
Hydrogen Peroxide	increases expression, affects cotreatment	1
Indomethacin	affects cotreatment, increases expression	1
Lead	decreases expression	1
Pesticides	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Theophylline	affects cotreatment, increases expression	1
Thiram	increases expression	1

ChEMBL screening assays

155 unique, capped per target: 153 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3111726	Binding	Inhibition of WHSC1L (unknown origin)-mediated incorporation of methyl group from [3H]-SAM into peptide substrate up to 50 uM after 1 hr by scintillation proximity assay	Discovery and development of potent and selective inhibitors of histone methyltransferase g9a. — ACS Med Chem Lett
CHEMBL5444429	Functional	Affinity Phenotypic Cellular interaction: (RealTime-Glow MT Cell Viability Assay (proliferation of RN2 cells)) EUB0000270b NSD3	Affinity Phenotypic Cellular Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TY02	HAP1 WHSC1L1 (-) 1	Cancer cell line	Male
CVCL_TY03	HAP1 WHSC1L1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07050186	PHASE2	RECRUITING	Cemiplimab for the Treatment of Incurable Metastatic or Unresectable NUT Carcinoma
NCT02259114	PHASE1	COMPLETED	A Dose-Finding Study of Birabresib (MK-8628), a Small Molecule Inhibitor of the Bromodomain and Extra-Terminal (BET) Proteins, in Adults With Selected Advanced Solid Tumors (MK-8628-003)
NCT02307240	PHASE1	COMPLETED	Open Label, Multi-center Study to Assess the Safety, Tolerability and Pharmacokinetics of CUDC-907 in Subjects With Advanced/Relapsed Solid Tumors
NCT02516553	PHASE1	COMPLETED	BI 894999 First in Human Dose Finding Study in Advanced Malignancies
NCT02698176	PHASE1	TERMINATED	A Dose Exploration Study With Birabresib (MK-8628) in Participants With Selected Advanced Solid Tumors (MK-8628-006)
NCT05372640	PHASE1	RECRUITING	Testing the Safety and Efficacy of the Combination of Two Anti-cancer Drugs, ZEN003694 and Abemaciclib, for Adult and Pediatric Patients (12-17 Years) With Metastatic or Unresectable NUT Carcinoma, Breast Cancer and Other Solid Tumors
NCT05488548	PHASE1	RECRUITING	Dual BET and CBP/p300 Inhibitor in Patients With Targeted Advanced Solid Tumors and Hematological Malignancies
NCT04116359	PHASE1/PHASE2	WITHDRAWN	Testing of the Addition of a New Anti-cancer Drug, Molibresib, to Chemotherapy Treatment (Etoposide and Cisplatin) for Patients With NUT Carcinoma
NCT05019716	PHASE1/PHASE2	RECRUITING	Testing the Safety and Efficacy of the Addition of a New Anti-cancer Drug, ZEN003694, to Chemotherapy Treatment (Cisplatin and Etoposide or Carboplatin and Paclitaxel) for Adult and Pediatric Patients (12-17 Years) With NUT Carcinoma
NCT05265429	Not specified	RECRUITING	Biology of Young Lung Cancer Study: The YOUNG LUNG Study
NCT05812027	Not specified	ACTIVE_NOT_RECRUITING	A Screening Study to Collect Samples for TAA, HLA & HLA Loss of Heterozygosity in Patients With Metastatic Solid Tumors
NCT07072143	Not specified	RECRUITING	An International Study on Pediatric Patients With Rare Tumors.
NCT07459127	Not specified	ACTIVE_NOT_RECRUITING	Multicenter Retrospective Cohort of Pulmonary NUT Carcinoma