DOT1L

Summary

DOT1L (DOT1 like histone lysine methyltransferase, HGNC:24948) is a protein-coding gene on chromosome 19p13.3, encoding Histone-lysine N-methyltransferase, H3 lysine-79 specific (Q8TEK3). Histone methyltransferase that methylates ‘Lys-79’ of histone H3. It is a selective cancer dependency (DepMap: 12.1% of cell lines).

The protein encoded by this gene is a histone methyltransferase that methylates lysine-79 of histone H3. It is inactive against free core histones, but shows significant histone methyltransferase activity against nucleosomes.

Source: NCBI Gene 84444 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Strong, GenCC)
• GWAS associations: 44
• Clinical variants (ClinVar): 350 total — 8 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 103
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 2 cancer types
• Cancer dependency (DepMap): dependent in 12.1% of screened cell lines
• MANE Select transcript: NM_032482

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24948
Approved symbol	DOT1L
Name	DOT1 like histone lysine methyltransferase
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1814, DOT1, KMT4
Ensembl gene	ENSG00000104885
Ensembl biotype	protein_coding
OMIM	607375
Entrez	84444

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 6 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000398665, ENST00000452696, ENST00000457590, ENST00000478937, ENST00000482433, ENST00000586024, ENST00000591498, ENST00000608122, ENST00000686010, ENST00000936177

RefSeq mRNA: 2 — MANE Select: NM_032482 NM_001411141, NM_032482

CCDS: CCDS42460, CCDS92483

Canonical transcript exons

ENST00000398665 — 28 exons

Exon	Start	End
ENSE00000663807	2194515	2194577
ENSE00000663808	2199884	2199939
ENSE00000663809	2202700	2202779
ENSE00000663810	2206729	2206797
ENSE00000663811	2207574	2207680
ENSE00000663812	2208935	2208976
ENSE00000663813	2210400	2210510
ENSE00000663814	2210621	2210855
ENSE00000663815	2211099	2211212
ENSE00000663817	2211751	2211842
ENSE00000663821	2216281	2216765
ENSE00001055992	2225388	2225452
ENSE00001056006	2223281	2223486
ENSE00001056008	2220108	2220222
ENSE00001150583	2221976	2222559
ENSE00001150617	2226183	2227127
ENSE00001215883	2163933	2164265
ENSE00001760133	2229785	2232578
ENSE00003496774	2191012	2191240
ENSE00003512787	2193689	2193783
ENSE00003577090	2213539	2213640
ENSE00003580373	2216955	2217090
ENSE00003612873	2217772	2217918
ENSE00003613035	2189732	2189795
ENSE00003707214	2213849	2213986
ENSE00003707279	2214471	2214596
ENSE00003723467	2180713	2180756
ENSE00003734033	2185855	2185929

Expression profiles

Bgee: expression breadth ubiquitous, 194 present calls, max score 97.05.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.2456 / max 492.2215, expressed in 1820 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
173034	25.9767	1816
173035	6.5797	1338
173036	1.6690	640
173037	0.0202	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	97.05	gold quality
left testis	UBERON:0004533	97.03	gold quality
ileal mucosa	UBERON:0000331	93.94	gold quality
testis	UBERON:0000473	93.54	gold quality
ventricular zone	UBERON:0003053	91.19	gold quality
sural nerve	UBERON:0015488	91.01	gold quality
ganglionic eminence	UBERON:0004023	90.01	gold quality
sperm	CL:0000019	88.83	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.36	gold quality
metanephros cortex	UBERON:0010533	88.11	gold quality
lower esophagus mucosa	UBERON:0035834	86.81	gold quality
cerebellar hemisphere	UBERON:0002245	86.79	gold quality
right lobe of thyroid gland	UBERON:0001119	86.72	gold quality
mucosa of transverse colon	UBERON:0004991	86.65	gold quality
cerebellar cortex	UBERON:0002129	86.48	gold quality
small intestine Peyer’s patch	UBERON:0003454	86.05	gold quality
upper lobe of left lung	UBERON:0008952	85.95	gold quality
granulocyte	CL:0000094	85.83	gold quality
cortical plate	UBERON:0005343	85.74	gold quality
left lobe of thyroid gland	UBERON:0001120	85.48	gold quality
bone marrow cell	CL:0002092	85.31	gold quality
upper lobe of lung	UBERON:0008948	84.92	gold quality
adult organism	UBERON:0007023	84.75	gold quality
body of stomach	UBERON:0001161	84.57	gold quality
left adrenal gland cortex	UBERON:0035825	84.52	gold quality
right lobe of liver	UBERON:0001114	84.47	gold quality
cerebellum	UBERON:0002037	84.38	gold quality
adenohypophysis	UBERON:0002196	84.31	gold quality
transverse colon	UBERON:0001157	84.26	gold quality
spleen	UBERON:0002106	84.20	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	14.69

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

8 targets.

Target	Regulation
BCL2	Activation
HECTD4	Repression
HOXA9	Activation
IRF1	Activation
MCL1	Activation
MEIS1	Activation
MYCBP2	Repression
STAT1	Activation

Upstream regulators (CollecTRI, top): CREB1, FOXC1, IRF1, NR3C2, TBX15

miRNA regulators (miRDB)

94 targeting DOT1L, 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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-371A-3P	99.99	66.77	91
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6764-5P	99.75	67.89	2304

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 12.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• mistargeting of hDOT1L to Hoxa9 plays an important role in MLL-AF10-mediated leukemogenesis (PMID:15851025)
• Altered phosphorylation of histone-H3 is associated with hepatocarcinogenesis (PMID:17094487)
• Identification of ENL-associated proteins by mass spectrometry revealed enzymes with a known role in transcriptional elongation: pTEFb and DOT1L. (PMID:17855633)
• suggesting a widespread mechanism for parallel or sequential recruitment of DOT1L and MLL to genes in their normal “on” state (PMID:18285465)
• demonstration, using chemically ubiquitylated H2B, of a direct stimulation of hDot1L-mediated intranucleosomal methylation of H3 K79 (PMID:18449190)
• the CALM-AF10 fusion protein can also greatly reduce global H3K79 methylation in both human and murine leukemic cells by disrupting the AF10-mediated association of hDOT1L with chromatin (PMID:19443658)
• Impaired recruitment of the histone methyltransferase DOT1L contributes to the incomplete reactivation of tumor suppressor genes upon DNA demethylation. (PMID:19734945)
• titration of the level of ubiquitylated histone H2B within the nucleosome revealed a 1:1 stoichiometry of Dot1L activation. (PMID:19799466)
• AF17 competes with AF9 to bind Dot1a, decreases Dot1a nuclear expression by possibly facilitating its nuclear export, and relieves Dot1a.AF9-mediated repression of alpha-ENaC and other target genes. (PMID:19864429)
• study describes for the first time the components of DotCom and links the specific regulation of H3K79 trimethylation by Dot1 and its associated factors to the Wnt/Wingless signaling pathway (PMID:20203130)
• This permitted structure-activity studies of ubiquitylated mononucleosomes that revealed plasticity in the mechanism of hDot1L stimulation and identified surfaces of ubiquitin important for activation. (PMID:20208522)
• These data point to DOT1L as a potential therapeutic target in MLL-rearranged leukemia. (PMID:21741597)
• a novel STAT1-DOT1L interaction that is required for the regulation JAK-STAT-inducible gene expression (PMID:22002246)
• down-regulation of DOT1L-mediated H3K79 methylation disturbs proliferation of human cells (PMID:22190683)
• These findings identify a novel role for Bat3 in regulating DOT1L function, which plays a critical role in DNA damage response. (PMID:22373577)
• These data are a further step to better understand the role of Wnt-signaling during chondrogenesis and cartilage homeostasis. DOT1L may represent a therapeutic target for osteoarthritis. (PMID:22566624)
• Data show that histone monoubiquitylation H2Aub did not influence histone methyltransferase Dot1L activity. (PMID:22619169)
• a functional interaction between hDOT1L and RNAPII targets hDOT1L and subsequent H3K79 methylations to actively transcribed genes. (PMID:23012353)
• In male subjects, the rs12982744 polymorphism in DOT1L is associated with hip osteoarthritis. (PMID:23505243)
• Interaction with CBX8 precludes AF9-DOT1L binding. (PMID:23891621)
• Functional studies show that the mapped AF9/ENL interacting site is essential for immortalization by MLL-AF9, indicating that DOT1L interaction with MLL-AF9 and its recruitment are required for transformation by MLL-AF9. (PMID:23996074)
• PITX2 forms complex with histone H3 lysine 4 (H3K4) methyltransferase. PITX2 complex methylates H3K4. (PMID:24486544)
• DOT1L Regulates IL-22 Dependent Colon Cancer Stemness via H3K79 Methylation (PMID:24816405)
• Establishing the precise function of DOT1L in normal adult hematopoiesis and understanding its mode of action will aid in our understanding of the use of DOT1L as a therapeutic target in MLL-rearranged leukemia. (PMID:24854991)
• inhibition of DOT1L, in combination with DNA damaging chemotherapy, represents a promising approach to improving outcomes for MLL-rearranged leukemia. (PMID:24858818)
• A genome-wide association study identifies PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for myocardial infarction in Japanese (PMID:24916648)
• DOT1L rs12982744 G to C change and variant C genotype may contribute to knee OA risk in a Chinese Han population. (PMID:25005768)
• Studies identified the evolutionarily conserved Af9 YEATS domain as a novel acetyllysine-binding module and established a direct link between histone acetylation and DOT1L-mediated H3K79 methylation in transcription control. (PMID:25417107)
• Results provide evidence that transformation driven by MLL fusions as well as the recurrent AML-associated NUP98-NSD1 fusion oncogene is critically dependent on the ability of AF10 to stimulate DOT1L activity. (PMID:25464900)
• Three candidate variants were identified: p.Glu1313Lys in Insulin receptor (INSR), p.Arg81Pro in F-box protein 24 (FBXO24) and p.Pro1146Leu in DOT1-like histone H3K79 methyltransferase (PMID:25576241)
• The graded reduction of the DOT1L interaction with MLL-AF9 results in differential loss of H3K79me2 and me3 at MLL-AF9 target genes. (PMID:25921540)
• Targeting DOT1L and HOX gene expression in MLL-rearranged leukemia and beyond. (PMID:26118503)
• expression associated with poorer survival and aggressiveness of breast cancers (PMID:26199140)
• analysis of a functional hotspot on ubiquitin that is required for the stimulation of human Dot1 (PMID:26240340)
• Report drug formulation/delivery of DOT1L inhibitor pinometostat in leukemia. (PMID:26385168)
• The PZP domain of AF10 senses unmodified H3K27 to regulate DOT1L-mediated methylation of H3K79. (PMID:26439302)
• These data converge on a possible mechanism for hDot1L stimulation in which histone H2B physically ‘corrals’ the enzyme into a productive binding orientation. (PMID:26830124)
• study demonstrates the development of potent DOT1L inhibitors with novel scaffolds (PMID:26914852)
• this indicates that DOT1L function, like MLL, does not completely rely on its methyltransferase activity. Nevertheless, the small molecule DOT1L inhibition is sufficient to block the proliferation of MLL fusion-induced leukemia cells of murine and human origin (PMID:26923329)
• MLL1 and DOT1L cooperate with meningioma-1 to induce acute myeloid leukemia. (PMID:26927674)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	dot1l	ENSDARG00000061992
mus_musculus	Dot1l	ENSMUSG00000061589
rattus_norvegicus	Dot1l	ENSRNOG00000032546
drosophila_melanogaster	gpp	FBGN0264495
caenorhabditis_elegans		WBGENE00008367
caenorhabditis_elegans		WBGENE00010067
caenorhabditis_elegans		WBGENE00010120
caenorhabditis_elegans		WBGENE00012302
caenorhabditis_elegans	dot-1.1	WBGENE00021474
caenorhabditis_elegans		WBGENE00022512

Protein

Protein identifiers

Histone-lysine N-methyltransferase, H3 lysine-79 specific — Q8TEK3 (reviewed: Q8TEK3)

Alternative names: DOT1-like protein, Disruptor of telomeric silencing 1-like histone lysine methyltransferase, Histone H3-K79 methyltransferase, Lysine N-methyltransferase 4

All UniProt accessions (6): Q8TEK3, A0A087X1A7, A0A8I5QL06, C9JH95, H7C2S2, V9GY76

UniProt curated annotations — full annotation on UniProt →

Function. Histone methyltransferase that methylates ‘Lys-79’ of histone H3. Nucleosomes are preferred as substrate compared to free histones. Binds to DNA.

Subunit / interactions. Interacts with MLLT10.

Subcellular location. Nucleus.

Disease relevance. Nil-Deshwar neurodevelopmental syndrome (NDNS) [MIM:621265] An autosomal dominant neurodevelopmental disorder characterized by global developmental delay, impaired intellectual development, poor or absent speech, hypotonia, and various heterogeneous congenital anomalies, including brain, cardiac and urogenital abnormalities. The disease is caused by variants affecting the gene represented in this entry. Disease-causing variants may act through a gain-of-function effect leading to an increase in cellular H3K79 methylation levels.

Activity regulation. Inhibited by EPZ00477747 compound, a chemical derivative of S-adenosyl-L-methionine (SAM).

Induction. (Microbial infection) Expression is down-regulated following M.tuberculosis infection, hence decreasing DOT1L-mediated nucleosomally added H3K79me3 mark on pro-inflammatory response genes.

Miscellaneous. In contrast to other lysine histone methyltransferases, it does not contain a SET domain, suggesting the existence of another mechanism for methylation of lysine residues of histones.

Similarity. Belongs to the class I-like SAM-binding methyltransferase superfamily. DOT1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8TEK3-2	1	yes
Q8TEK3-1	2

RefSeq proteins (2): NP_001398070, NP_115871* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR021169	DOT1L/grappa	Family
IPR025789	DOT1_dom	Domain
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily
IPR030445	H3-K79_meTrfase	Family

Pfam: PF08123

Enzyme classification (BRENDA):

• EC 2.1.1.355 — [histone H3]-lysine9 N-trimethyltransferase (BRENDA: 12 organisms, 83 substrates, 52 inhibitors, 11 Km, 11 kcat entries)
• EC 2.1.1.360 — [histone H3]-lysine79 N-trimethyltransferase (BRENDA: 7 organisms, 20 substrates, 9 inhibitors, 0 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

10 substrates with measured Km, best-characterized 10. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
HISTONE H3	0.0003–0.0009	2
BIOTINYL-MARTKQTARKSTGGKAPRKQ	0.0074	1
HISTONE H3 (1-13)	0.0011	1
HISTONE H3 (T11PHOS)	0.0006	1
HISTONE H3(K27A)	0.0002	1
HISTONE H3(K4A)	0.0002	1
HISTONE K4-ACETYLK9	0.0022	1
HISTONE K4-TRIMETHYLK9	0.0006	1
HISTONE K4AK9	0.0015	1
HISTONE H3 (S10PHOS)	—	0

Catalyzed reactions (Rhea), 1 shown:

• L-lysyl(79)-[histone H3] + 3 S-adenosyl-L-methionine = N(6),N(6),N(6)-trimethyl-L-lysyl(79)-[histone H3] + 3 S-adenosyl-L-homocysteine + 3 H(+) (RHEA:60328)

UniProt features (108 total): modified residue 20, strand 19, helix 17, compositionally biased region 13, sequence variant 12, region of interest 8, mutagenesis site 5, turn 4, binding site 4, sequence conflict 3, chain 1, domain 1, splice variant 1

Structure

Experimental structures (PDB)

48 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
7S7F	X-RAY DIFFRACTION	1.88
6TE6	X-RAY DIFFRACTION	1.98
7S7E	X-RAY DIFFRACTION	2.04
3UWP	X-RAY DIFFRACTION	2.05
5MW3	X-RAY DIFFRACTION	2.09
3QOW	X-RAY DIFFRACTION	2.1
4EQZ	X-RAY DIFFRACTION	2.15
5MVS	X-RAY DIFFRACTION	2.18
5MW4	X-RAY DIFFRACTION	2.19
6TEL	X-RAY DIFFRACTION	2.19
4ER7	X-RAY DIFFRACTION	2.2
5DTM	X-RAY DIFFRACTION	2.2
7EDP	X-RAY DIFFRACTION	2.2
6TEN	X-RAY DIFFRACTION	2.21
3SX0	X-RAY DIFFRACTION	2.28
5JUW	X-RAY DIFFRACTION	2.28
3QOX	X-RAY DIFFRACTION	2.3
4ER6	X-RAY DIFFRACTION	2.3
5DT2	X-RAY DIFFRACTION	2.3
6IN3	X-RAY DIFFRACTION	2.3
5DTR	X-RAY DIFFRACTION	2.34
4ER3	X-RAY DIFFRACTION	2.4
4WVL	X-RAY DIFFRACTION	2.41
5DRY	X-RAY DIFFRACTION	2.41
5DSX	X-RAY DIFFRACTION	2.41
1NW3	X-RAY DIFFRACTION	2.5
3SR4	X-RAY DIFFRACTION	2.5
4EK9	X-RAY DIFFRACTION	2.5
4ER0	X-RAY DIFFRACTION	2.5
4ER5	X-RAY DIFFRACTION	2.57

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TEK3-F1	54.11	0.20

Functional residue map

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

Ligand- & substrate-binding residues (4): 136–139; 159–168; 186; 222–223

Post-translational modifications (20): 297, 374, 448, 471, 480, 775, 786, 826, 834, 900, 902, 984, 997, 1001, 1009, 1035, 1093, 1104, 1213, 1246

Mutagenesis-validated functional residues (5):

Position	Phenotype
163–165	abolishes methyltransferase activity.
241	loss of activity.
270	reduces methyltransferase activity.
312	loss of activity.
312	no effect.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-3214841	PKMTs methylate histone lysines

MSigDB gene sets: 162 (showing top): GOBP_CHROMOSOME_ORGANIZATION, GOBP_CELL_CYCLE_PHASE_TRANSITION, GCAAGGA_MIR502, GOBP_TELOMERE_ORGANIZATION, GOBP_CELL_SURFACE_RECEPTOR_SIGNALING_PATHWAY_VIA_JAK_STAT, CTATGCA_MIR153, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE, GOBP_REGULATION_OF_CELL_CYCLE, GOBP_DNA_DAMAGE_RESPONSE, KEGG_LYSINE_DEGRADATION, HIF1_Q3, GOBP_SIGNAL_TRANSDUCTION_IN_RESPONSE_TO_DNA_DAMAGE

GO Biological Process (15): DNA damage checkpoint signaling (GO:0000077), DNA repair (GO:0006281), sodium ion transport (GO:0006814), gene expression (GO:0010467), subtelomeric heterochromatin formation (GO:0031509), telomere organization (GO:0032200), methylation (GO:0032259), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of receptor signaling pathway via JAK-STAT (GO:0046425), regulation of transcription regulatory region DNA binding (GO:2000677), chromatin organization (GO:0006325), chromatin remodeling (GO:0006338), heterochromatin formation (GO:0031507), positive regulation of DNA-templated transcription (GO:0045893), regulation of cell cycle (GO:0051726)

GO Molecular Function (11): nucleic acid binding (GO:0003676), DNA binding (GO:0003677), transcription coactivator activity (GO:0003713), histone H3K79 methyltransferase activity (GO:0031151), histone methyltransferase activity (GO:0042054), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), histone H3 methyltransferase activity (GO:0140938), histone H3K79 trimethyltransferase activity (GO:0140956), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740)

GO Cellular Component (5): chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), protein-containing complex (GO:0032991)

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
positive regulation of DNA-templated transcription	2
binding	2
cellular anatomical structure	2
DNA integrity checkpoint signaling	1
signal transduction in response to DNA damage	1
DNA metabolic process	1
DNA damage response	1
metal ion transport	1
macromolecule biosynthetic process	1
chromosome, telomeric region	1
constitutive heterochromatin formation	1
chromosome organization	1
metabolic process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
cell surface receptor signaling pathway via JAK-STAT	1
regulation of receptor signaling pathway via STAT	1
transcription cis-regulatory region binding	1
regulation of DNA binding	1
cellular component organization	1
chromatin organization	1
cellular component assembly	1
heterochromatin boundary formation	1
negative regulation of gene expression, epigenetic	1
heterochromatin organization	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
cell cycle	1
regulation of cellular process	1
nucleic acid binding	1
transcription coregulator activity	1
protein-lysine N-methyltransferase activity	1
histone H3 methyltransferase activity	1
protein methyltransferase activity	1
histone modifying activity	1
DNA-binding transcription factor binding	1
histone methyltransferase activity	1
histone H3K79 methyltransferase activity	1
transferase activity, transferring one-carbon groups	1

Protein interactions and networks

STRING

2275 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DOT1L	MLLT10	P55197	994
DOT1L	MLLT3	P42568	990
DOT1L	MLLT1	Q03111	984
DOT1L	AFF1	P51825	933
DOT1L	BRD4	O60885	869
DOT1L	SETD1A	O15047	853
DOT1L	EZH2	Q15910	853
DOT1L	MYC	P01106	852
DOT1L	H3-3A	P06351	848
DOT1L	H3C1	P02295	848
DOT1L	H3C14	Q71DI3	837
DOT1L	H3-5	Q6NXT2	837
DOT1L	H3-4	Q16695	837
DOT1L	H3-7	Q5TEC6	837
DOT1L	H2BC21	Q16778	824

IntAct

49 interactions, top by confidence:

A	B	Type	Score
MLLT3	DOT1L	psi-mi:“MI:0915”(physical association)	0.820
MLLT3	DOT1L	psi-mi:“MI:0407”(direct interaction)	0.820
DOT1L	MLLT3	psi-mi:“MI:0914”(association)	0.820
DOT1L	MLLT3	psi-mi:“MI:0915”(physical association)	0.820
DOT1L	MLLT10	psi-mi:“MI:0915”(physical association)	0.770
PRKD2	PRKD3	psi-mi:“MI:0914”(association)	0.730
MLLT1	DOT1L	psi-mi:“MI:0915”(physical association)	0.680
DOT1L	MLLT1	psi-mi:“MI:0915”(physical association)	0.680
MLLT1	DOT1L	psi-mi:“MI:0914”(association)	0.680
CTNNB1	MLLT10	psi-mi:“MI:0914”(association)	0.660
DOT1L	CTNNB1	psi-mi:“MI:0915”(physical association)	0.560
MLLT6	RGPD8	psi-mi:“MI:0914”(association)	0.530
DAXX	TNRC18	psi-mi:“MI:0914”(association)	0.530
Mllt3	DOT1L	psi-mi:“MI:0407”(direct interaction)	0.440
H3C13	DOT1L	psi-mi:“MI:0213”(methylation reaction)	0.440
DOT1L	HMOX2	psi-mi:“MI:0915”(physical association)	0.400
DOT1L		psi-mi:“MI:0915”(physical association)	0.400
	DOT1L	psi-mi:“MI:0915”(physical association)	0.400
DOT1L	IBTK	psi-mi:“MI:0914”(association)	0.350
MLLT10	TCF4	psi-mi:“MI:0914”(association)	0.350
TCF4	MLLT10	psi-mi:“MI:0914”(association)	0.350
DOT1L	TCF4	psi-mi:“MI:0914”(association)	0.350
MLLT10	SOD1	psi-mi:“MI:0914”(association)	0.350
	AFF1	psi-mi:“MI:0914”(association)	0.350

BioGRID (894): MLLT6 (Co-fractionation), DOT1L (Synthetic Growth Defect), MLLT3 (Affinity Capture-MS), MLLT6 (Affinity Capture-MS), MAPK7 (Affinity Capture-MS), MLLT10 (Affinity Capture-MS), EBNA1BP2 (Affinity Capture-MS), IBTK (Affinity Capture-MS), NIN (Affinity Capture-MS), PARP16 (Affinity Capture-MS), DOT1L (Affinity Capture-MS), DOT1L (Affinity Capture-MS), DOT1L (Affinity Capture-MS), DOT1L (Affinity Capture-MS), DOT1L (Affinity Capture-MS)

ESM2 similar proteins: A0A088MLT8, A2AQ25, B3KU38, B5DF41, E9PSK7, O15079, O35274, P0DPB3, P0DPB4, P12755, P49140, P85299, Q0D2I5, Q14DQ1, Q1LY51, Q3B7M3, Q3SYW5, Q4KMA0, Q4R3X1, Q50H33, Q5F3L9, Q5FVG6, Q5RD40, Q5XKK7, Q60698, Q6ZNC4, Q6ZUS6, Q6ZWB6, Q80U23, Q80U62, Q80XA6, Q812A5, Q86YI8, Q8BXL9, Q8K2W6, Q8ND83, Q8NFH8, Q8QFX1, Q8TEK3, Q924W7

Diamond homologs: P0CN14, P0CN15, Q1DKD8, Q2H9L1, Q2U696, Q4IJP1, Q4P2W8, Q4WVH4, Q5A309, Q6BTC8, Q6C4Y5, Q756E1, Q7SB74, Q8INR6, Q8TEK3, Q04089, Q5BH89, Q6CWV1, Q6FNM5, Q6AW06, Q55AX2

SIGNOR signaling

15 interactions.

A	Effect	B	Mechanism
DOT1L	“up-regulates activity”	MYC	binding
MLL-AF4	“up-regulates activity”	DOT1L	binding
DOT1L	“up-regulates quantity by expression”	BCL2	“transcriptional regulation”
DOT1L	“up-regulates quantity by expression”	MCL1	“transcriptional regulation”
DOT1L	“up-regulates quantity by expression”	HOXA9	“transcriptional regulation”
DOT1L	“up-regulates quantity by expression”	MEIS1	“transcriptional regulation”
“MLL Fusion”	“up-regulates activity”	DOT1L	binding
DOT1L	unknown	H3C1	methylation
DOT1L	unknown	H3-4	methylation
DOT1L	unknown	H3-3A	methylation
DOT1L	“down-regulates quantity by repression”	HECTD4	“transcriptional regulation”
DOT1L	“down-regulates quantity by repression”	MYCBP2	“transcriptional regulation”
MLL-AF9	“up-regulates activity”	DOT1L	binding
MLL-ENL	“up-regulates activity”	DOT1L	binding

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 2 cancer types — DLBCLNOS, NBL.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	1
Uncertain significance	228
Likely benign	68
Benign	10

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
3359220	NM_032482.3(DOT1L):c.299C>T (p.Thr100Met)	Pathogenic
4056361	NM_032482.3(DOT1L):c.133T>G (p.Cys45Gly)	Pathogenic
4056363	NM_032482.3(DOT1L):c.367G>A (p.Glu123Lys)	Pathogenic
4056364	NM_032482.3(DOT1L):c.385G>A (p.Glu129Lys)	Pathogenic
4056365	NM_032482.3(DOT1L):c.1876C>G (p.Leu626Val)	Pathogenic
4056366	NM_032482.3(DOT1L):c.2557C>T (p.Arg853Cys)	Pathogenic
4056367	NM_032482.3(DOT1L):c.3074A>T (p.Lys1025Met)	Pathogenic
4813224	NM_032482.3(DOT1L):c.469G>A (p.Asp157Asn)	Pathogenic
986228	NM_032482.3(DOT1L):c.3882dup (p.Gly1295fs)	Likely pathogenic

SpliceAI

5901 predictions. Top by Δscore:

Variant	Effect	Δscore
19:2164266:G:GG	donor_gain	1.0000
19:2180707:TTTCA:T	acceptor_loss	1.0000
19:2180708:TTCAG:T	acceptor_loss	1.0000
19:2180709:TCAGG:T	acceptor_loss	1.0000
19:2180710:CAGG:C	acceptor_loss	1.0000
19:2180711:A:T	acceptor_loss	1.0000
19:2180711:AG:A	acceptor_gain	1.0000
19:2180712:G:A	acceptor_loss	1.0000
19:2180712:GG:G	acceptor_gain	1.0000
19:2180754:CCGGT:C	donor_loss	1.0000
19:2180755:CGGTG:C	donor_loss	1.0000
19:2180756:GGTG:G	donor_loss	1.0000
19:2180757:G:A	donor_loss	1.0000
19:2180757:G:GG	donor_gain	1.0000
19:2180758:T:G	donor_loss	1.0000
19:2180759:G:GG	donor_loss	1.0000
19:2185853:AGATG:A	acceptor_gain	1.0000
19:2185854:GATGG:G	acceptor_gain	1.0000
19:2189727:TTCA:T	acceptor_loss	1.0000
19:2189730:A:AG	acceptor_gain	1.0000
19:2189730:AGCT:A	acceptor_loss	1.0000
19:2189731:G:GG	acceptor_gain	1.0000
19:2189792:GCTG:G	donor_gain	1.0000
19:2189795:GGTA:G	donor_loss	1.0000
19:2189796:G:GG	donor_gain	1.0000
19:2189797:T:A	donor_loss	1.0000
19:2191010:AGT:A	acceptor_gain	1.0000
19:2191011:GT:G	acceptor_gain	1.0000
19:2191011:GTG:G	acceptor_gain	1.0000
19:2191011:GTGGA:G	acceptor_gain	1.0000

AlphaMissense

9973 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:2164204:T:C	L7P	1.000
19:2164210:T:C	L9P	1.000
19:2164248:T:A	W22R	1.000
19:2164248:T:C	W22R	1.000
19:2164250:G:C	W22C	1.000
19:2164250:G:T	W22C	1.000
19:2180741:T:G	I37S	1.000
19:2180753:T:A	I41N	1.000
19:2180756:G:C	R42P	1.000
19:2185856:T:A	W43R	1.000
19:2185856:T:C	W43R	1.000
19:2185860:T:A	V44D	1.000
19:2185863:G:A	C45Y	1.000
19:2185864:T:G	C45W	1.000
19:2185881:T:A	L51H	1.000
19:2185881:T:C	L51P	1.000
19:2185890:C:A	A54D	1.000
19:2189752:T:C	L74P	1.000
19:2189763:T:G	Y78D	1.000
19:2189773:C:A	A81D	1.000
19:2189794:T:C	L88P	1.000
19:2191012:T:A	W89R	1.000
19:2191012:T:C	W89R	1.000
19:2191079:T:C	L111P	1.000
19:2191121:T:A	L125H	1.000
19:2191121:T:C	L125P	1.000
19:2191129:T:C	Y128H	1.000
19:2191138:T:A	F131I	1.000
19:2191138:T:C	F131L	1.000
19:2191138:T:G	F131V	1.000

dbSNP variants (sampled 300 via entrez): RS1000003642 (19:2190326 C>T), RS1000004085 (19:2171769 T>C), RS1000052391 (19:2218662 G>A), RS1000091927 (19:2222666 C>A,T), RS1000113411 (19:2177790 C>G), RS1000113788 (19:2167555 G>A,T), RS1000189595 (19:2231792 C>G,T), RS1000211839 (19:2194321 C>A,G,T), RS1000223000 (19:2163427 G>C), RS1000255502 (19:2198491 C>T), RS1000275190 (19:2163672 C>A,T), RS1000304103 (19:2176881 T>C), RS1000309169 (19:2198307 G>T), RS1000363810 (19:2192511 A>G), RS1000460757 (19:2196416 T>C)

Disease associations

OMIM: gene MIM:607375 | disease phenotypes: MIM:621265

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Strong	Autosomal dominant

Mondo (2): Nil-Deshwar neurodevelopmental syndrome (MONDO:0979246), neurodevelopmental disorder (MONDO:0700092)

Orphanet (0):

HPO phenotypes

103 total (30 of 103 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000041	Chordee
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000218	High palate
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000260	Wide anterior fontanel
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000293	Full cheeks
HP:0000303	Mandibular prognathia
HP:0000307	Pointed chin
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000365	Hearing impairment
HP:0000402	Stenosis of the external auditory canal
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000414	Bulbous nose
HP:0000431	Wide nasal bridge
HP:0000452	Choanal stenosis
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000581	Blepharophimosis
HP:0000582	Upslanted palpebral fissure
HP:0000609	Optic nerve hypoplasia

GWAS associations

44 associations (top):

Study	Trait	p-value
GCST000176_4	Height	3.000000e-08
GCST000817_95	Height	3.000000e-16
GCST001516_1	Osteoarthritis	1.000000e-11
GCST001956_65	Height	2.000000e-12
GCST002475_3	Myocardial infarction	4.000000e-09
GCST002647_158	Height	7.000000e-28
GCST003274_10	Pulse pressure	3.000000e-15
GCST003853_1	Hip minimal joint space width	3.000000e-16
GCST004067_160	Hip circumference adjusted for BMI	3.000000e-13
GCST004067_218	Hip circumference adjusted for BMI	2.000000e-06
GCST004067_26	Hip circumference adjusted for BMI	9.000000e-16
GCST005994_5	Hematocrit	3.000000e-09
GCST005995_17	Hemoglobin	1.000000e-08
GCST005996_6	Red blood cell count	4.000000e-08
GCST006009_10	Pulse pressure	1.000000e-12
GCST006228_14	Systolic blood pressure	6.000000e-08
GCST006230_8	Pulse pressure	2.000000e-10
GCST006288_371	Heel bone mineral density	2.000000e-06
GCST006288_671	Heel bone mineral density	3.000000e-10
GCST006979_745	Heel bone mineral density	1.000000e-18
GCST007096_11	Pulse pressure	4.000000e-08
GCST007269_134	Pulse pressure	9.000000e-25
GCST007703_90	Systolic blood pressure	3.000000e-06
GCST007705_72	Pulse pressure	3.000000e-12
GCST007705_82	Pulse pressure	8.000000e-20
GCST008163_348	Height	3.000000e-08
GCST010083_281	Hemoglobin levels	2.000000e-39
GCST011492_1	Systemic lupus erythematosus	3.000000e-06
GCST011493_3	Systemic lupus erythematosus	8.000000e-09
GCST012227_680	Hip circumference adjusted for BMI	8.000000e-18

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0005763	pulse pressure measurement
EFO:0007873	cartilage thickness measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0004305	erythrocyte count
EFO:0006335	systolic blood pressure
EFO:0009270	heel bone mineral density
EFO:0004980	appendicular lean mass
EFO:0007985	platelet crit
EFO:0004309	platelet count
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1795117 (SINGLE PROTEIN), CHEMBL6195512 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 224,943 (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
CHEMBL477	ADENOSINE	4	222,014
CHEMBL1214186	SINEFUNGIN	2	2,165
CHEMBL3414626	PINOMETOSTAT	2	764

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2269879	Efficacy	3	hydrochlorothiazide	Hypertension
rs740406	Efficacy	3	candesartan	Hypertension

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2269879	DOT1L	3	0.50	1	hydrochlorothiazide
rs740406	DOT1L, PLEKHJ1	3	3.00	1	candesartan

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 (5 total), top 5:

Ligand	Action	Affinity	Parameter
pinometostat	Inhibition	10.1	pKi
compound 13 [Chen et al., 2016]	Inhibition	10.1	pKi
SGC0946	Inhibition	9.52	pIC50
EPZ004777	Inhibition	9.4	pIC50
bromo-deaza-SAH	Inhibition	7.11	pIC50

Binding affinities (BindingDB)

25 measured of 32 human assays (32 total across all organisms); most potent 25 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
1-[3-[[(2R,3S)-5-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxyoxolan-2-yl]methyl-propan-2-ylamino]propyl]-3-(4-tert-butylphenyl)urea	KD	0.01 nM	US-10112968: Inhibitors of protein methyltransferase DOT1L and methods of use thereof
EPZ004777	KD	0.1 nM
(2R,3R,4S,5R)-2-(6-aminopurin-9-yl)-5-[[[3-[2-[5-chloro-6-(trifluoromethyl)-1H-benzimidazol-2-yl]ethyl]cyclobutyl]-propan-2-ylamino]methyl]oxolane-3,4-diol	IC50	0.59 nM	US-9446064: Combination therapy for treating cancer
(2R,3R,4S,5R)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[[[3-[2-(6-tert-butyl-1H-benzimidazol-2-yl)ethyl]cyclobutyl]-propan-2-ylamino]methyl]oxolane-3,4-diol	IC50	0.59 nM	US-9446064: Combination therapy for treating cancer
(3S)-2-(6-aminopurin-9-yl)-5-[[[3-[2-[5-chloro-6-(trifluoromethyl)-1H-benzimidazol-2-yl]ethyl]cyclobutyl]-propan-2-ylamino]methyl]oxolane-3,4-diol	IC50	0.59 nM	US-10112968: Inhibitors of protein methyltransferase DOT1L and methods of use thereof
(2R,3R,4S,5R)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[[[3-[2-(6-tert-butyl-1H-benzimidazol-2-yl)ethyl]cyclobutyl]-methylamino]methyl]oxolane-3,4-diol	IC50	0.62 nM	US-9446064: Combination therapy for treating cancer
(2R,3R,4S,5R)-2-(6-aminopurin-9-yl)-5-[[[3-[2-(6-tert-butyl-1H-benzimidazol-2-yl)ethyl]cyclobutyl]-propan-2-ylamino]methyl]oxolane-3,4-diol	IC50	0.73 nM	US-9446064: Combination therapy for treating cancer
(3R)-2-(6-aminopurin-9-yl)-5-[[[3-[2-(6-tert-butyl-1H-benzimidazol-2-yl)ethyl]cyclobutyl]-propan-2-ylamino]methyl]oxolane-3,4-diol	IC50	0.73 nM	US-10112968: Inhibitors of protein methyltransferase DOT1L and methods of use thereof
(3S)-2-(6-aminopurin-9-yl)-5-[[[3-[2-(6-tert-butyl-1H-benzimidazol-2-yl)ethyl]cyclobutyl]-propan-2-ylamino]methyl]oxolane-3,4-diol	IC50	0.74 nM	US-10112968: Inhibitors of protein methyltransferase DOT1L and methods of use thereof
(2R,3R,4S,5R)-2-(6-aminopurin-9-yl)-5-[[[3-[2-(6-tert-butyl-1H-benzimidazol-2-yl)ethyl]cyclobutyl]-propan-2-ylamino]methyl]oxolane-3,4-diol	IC50	0.74 nM	US-9446064: Combination therapy for treating cancer
(2R,3R,4S,5R)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[[propan-2-yl-[3-[2-[6-(trifluoromethoxy)-1H-benzimidazol-2-yl]ethyl]cyclobutyl]amino]methyl]oxolane-3,4-diol	IC50	0.8 nM	US-9446064: Combination therapy for treating cancer
1-[3-[[(2R,3S,4R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl-methylamino]propyl]-3-(4-tert-butylphenyl)urea	KD	1.7 nM	US-10112968: Inhibitors of protein methyltransferase DOT1L and methods of use thereof
(2R,3R,4S,5R)-2-(6-aminopurin-9-yl)-5-[[propan-2-yl-[3-[2-[6-(trifluoromethoxy)-1H-benzimidazol-2-yl]ethyl]cyclobutyl]amino]methyl]oxolane-3,4-diol	IC50	2.18 nM	US-9446064: Combination therapy for treating cancer
(1R,2S,3R,5R)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[[[3-[2-(6-tert-butyl-1H-benzimidazol-2-yl)ethyl]cyclobutyl]-methylamino]methyl]cyclopentane-1,2-diol	IC50	2.51 nM	US-9446064: Combination therapy for treating cancer
(2R,3R,4S,5R)-2-(6-aminopurin-9-yl)-5-[[propan-2-yl-[3-[2-[6-(trifluoromethoxy)-1H-benzimidazol-2-yl]ethyl]cyclobutyl]amino]methyl]oxolane-3,4-diol	IC50	2.92 nM	US-9446064: Combination therapy for treating cancer
EPZ004450	KI	4 nM
1-[3-[[(3S,4R,5R)-5-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxyoxolan-2-yl]methyl-methylamino]propyl]-3-(4-tert-butylphenyl)urea	IC50	6 nM	US-8722877: 7-deazapurine modulators of histone methyltransferase, and methods of use thereof
EPZ003696	KI	13 nM
[(1R)-1-amino-3-[[(2S,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methylsulfanyl]propyl] formate	KD	71 nM	US-10112968: Inhibitors of protein methyltransferase DOT1L and methods of use thereof
SAH	KD	71 nM
1-[2-[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl-methylamino]ethyl]-3-(4-tert-butylphenyl)urea	KD	167 nM	US-10112968: Inhibitors of protein methyltransferase DOT1L and methods of use thereof
EPZ003647	KD	167 nM
EPZ002446	KI	12000 nM
EPZ003144	KI	20000 nM
EPZ000004	KI	38000 nM

ChEMBL bioactivities

253 potent at pChembl≥5 of 327 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	Kd	0.01	nM	CHEMBL5764114
10.92	Ki	0.012	nM	PINOMETOSTAT
10.25	Kd	0.0561	nM	CHEMBL3087498
10.22	Kd	0.06	nM	CHEMBL3087498
10.10	Ki	0.08	nM	PINOMETOSTAT
10.10	Ki	0.08	nM	CHEMBL4590355
9.96	IC50	0.11	nM	CHEMBL4446126
9.82	IC50	0.15	nM	CHEMBL4081752
9.77	IC50	0.17	nM	CHEMBL4435508
9.72	IC50	0.19	nM	CHEMBL4567485
9.60	Kd	0.25	nM	CHEMBL2169919
9.60	Kd	0.253	nM	CHEMBL2169919
9.52	IC50	0.3	nM	CHEMBL3087498
9.52	IC50	0.3	nM	CHEMBL5188291
9.52	IC50	0.3	nM	CHEMBL5176983
9.52	Ki	0.3	nM	CHEMBL5764114
9.44	Ki	0.36	nM	CHEMBL4534250
9.40	IC50	0.4	nM	CHEMBL2169919
9.40	IC50	0.4	nM	CHEMBL4590355
9.34	Ki	0.46	nM	CHEMBL2171169
9.30	Ki	0.5	nM	CHEMBL2171169
9.30	IC50	0.5	nM	CHEMBL2169919
9.23	IC50	0.59	nM	CHEMBL4112081
9.23	IC50	0.59	nM	CHEMBL4106621
9.23	IC50	0.59	nM	CHEMBL4557484
9.23	IC50	0.59	nM	CHEMBL5869844
9.21	IC50	0.62	nM	CHEMBL4114909
9.14	Ki	0.72	nM	CHEMBL2171169
9.14	IC50	0.73	nM	CHEMBL4079133
9.14	IC50	0.73	nM	CHEMBL5766448
9.13	IC50	0.74	nM	PINOMETOSTAT
9.13	IC50	0.74	nM	CHEMBL6031127
9.12	Ki	0.76	nM	CHEMBL2171170
9.10	Ki	0.8	nM	CHEMBL2171170
9.10	IC50	0.8	nM	CHEMBL4107547
9.07	IC50	0.86	nM	CHEMBL2169919
8.96	Ki	1.1	nM	CHEMBL3087503
8.89	Ki	1.3	nM	CHEMBL3087502
8.85	IC50	1.4	nM	CHEMBL4534250
8.77	Kd	1.7	nM	CHEMBL5792997
8.70	Kd	1.99	nM	CHEMBL2171169
8.68	IC50	2.1	nM	CHEMBL4448208
8.68	IC50	2.1	nM	CHEMBL5196874
8.66	IC50	2.18	nM	CHEMBL4108783
8.60	IC50	2.51	nM	CHEMBL4115320
8.59	IC50	2.6	nM	CHEMBL3087498
8.54	IC50	2.92	nM	CHEMBL4107217
8.54	ED50	2.9	nM	CHEMBL4435508
8.54	IC50	2.9	nM	CHEMBL2171169
8.52	IC50	3	nM	PINOMETOSTAT

PubChem BioAssay actives

236 with measured affinity, of 674 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
2-[[2-chloro-3-(2-methyl-3-pyridinyl)-1-benzothiophen-5-yl]carbamoylamino]-N-[3-[methyl-[(3R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl]amino]propyl]acetamide	1437357: Competitive inhibition of DOT1L (2 to 416 residues) (unknown origin) using biotinylated nucleosomes as substrate preincubated for 30 mins followed by substrate addition in presence of [3H-Me]SAM by scintillation proximity assay	ki	<0.0001	uM
(2R,3R,4S,5R)-2-(6-aminopurin-9-yl)-5-[[[3-[2-(6-tert-butyl-1H-benzimidazol-2-yl)ethyl]cyclobutyl]-propan-2-ylamino]methyl]oxolane-3,4-diol	1437357: Competitive inhibition of DOT1L (2 to 416 residues) (unknown origin) using biotinylated nucleosomes as substrate preincubated for 30 mins followed by substrate addition in presence of [3H-Me]SAM by scintillation proximity assay	ki	<0.0001	uM
4-N-methyl-2-N-[2-methyl-1-[2-(3-methylimidazo[4,5-b]pyridin-6-yl)oxyphenyl]indol-6-yl]pyrimidine-2,4-diamine	1637654: Inhibition of DOT1L (2 to 416 residues) (unknown origin) using biotinylated nucleosomes as substrate preincubated for 30 mins followed by substrate addition in presence of [3H-Me]SAM by scintillation proximity assay	ki	0.0001	uM
2-[[1-(2-chlorophenyl)indol-6-yl]carbamoylamino]-N-[3-[methyl-[(3R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl]amino]propyl]acetamide	1437352: Inhibition of DOT1L (2 to 416 residues) (unknown origin) using biotinylated nucleosomes as substrate preincubated for 30 mins followed by substrate addition in presence of [3H-Me]SAM by scintillation proximity assay	ic50	0.0001	uM
1-N-[(S)-(3-chloro-2-pyridinyl)-(2,2-difluoro-1,3-benzodioxol-4-yl)methyl]-2-N-(4-methoxy-6-piperazin-1-yl-1,3,5-triazin-2-yl)-4-methylsulfonylbenzene-1,2-diamine	1611846: Inhibition of 0.05 nM DOT1L (2 to 416 residues) (unknown origin) using biotinylated nucleosome as substrate and [3H]SAM as co-factor preincubated for 30 mins followed by substrate and cofactor addition and measured after 180 mins by scintillation proximity assay	ic50	0.0001	uM
1-[3-[[(2R,3S,4R,5R)-5-(4-amino-5-bromopyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxyoxolan-2-yl]methyl-propan-2-ylamino]propyl]-3-(4-tert-butylphenyl)urea	1199240: Binding affinity to DOT1L (unknown origin) by surface plasmon resonance analysis	kd	0.0001	uM
(2S,3S,4R,5S)-2-(6-aminopurin-9-yl)-5-[[[3-[2-(6-tert-butyl-1H-benzimidazol-2-yl)ethyl]cyclobutyl]-propan-2-ylamino]methyl]oxolane-3,4-diol	1882364: Binding affinity to DOT1L (unknown origin) assessed as inhibition constant	ki	0.0001	uM
3-[(4-amino-6-methoxy-1,3,5-triazin-2-yl)amino]-4-[[(S)-(3-chloro-2-pyridinyl)-(2,2-difluoro-1,3-benzodioxol-4-yl)methyl]amino]benzenesulfonamide	1611846: Inhibition of 0.05 nM DOT1L (2 to 416 residues) (unknown origin) using biotinylated nucleosome as substrate and [3H]SAM as co-factor preincubated for 30 mins followed by substrate and cofactor addition and measured after 180 mins by scintillation proximity assay	ic50	0.0002	uM
1-N-[(S)-(3-chloro-2-pyridinyl)-(2,2-difluoro-1,3-benzodioxol-4-yl)methyl]-2-N-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylsulfonylbenzene-1,2-diamine	1611846: Inhibition of 0.05 nM DOT1L (2 to 416 residues) (unknown origin) using biotinylated nucleosome as substrate and [3H]SAM as co-factor preincubated for 30 mins followed by substrate and cofactor addition and measured after 180 mins by scintillation proximity assay	ic50	0.0002	uM
1-[3-[[(2S,3R,4S,5S)-5-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxyoxolan-2-yl]methyl-propan-2-ylamino]propyl]-3-(4-tert-butylphenyl)urea	1882363: Inhibition of recombinant DOT1L (unknown origin) using 3H-SAM/chicken erythrocyte nucleosomes as substrate preincubated for 30 mins followed by substrate addition measured after 2 hrs by microplate reader method	ic50	0.0003	uM
1-[3-[[(2S,3R,4S,5S)-5-(4-amino-5-bromopyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxyoxolan-2-yl]methyl-propan-2-ylamino]propyl]-3-(4-tert-butylphenyl)urea	1882358: Inhibition of DOT1L (unknown origin)	ic50	0.0003	uM
1-[3-[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxyoxolan-2-yl]methyl-propan-2-ylamino]propyl]-3-(4-tert-butylphenyl)urea	1054112: Competitive inhibition of recombinant human DOT1L using adenosine/deazaadenosine as substrate and SAM cofactor	ki	0.0003	uM
1-[3-[[(3S,4R)-5-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxyoxolan-2-yl]methyl-propan-2-ylamino]propyl]-3-(4-tert-butylphenyl)urea	1799816: Enzyme Assay from Article 10.1111/cbdd.12050: “Conformational Adaptation Drives Potent, Selective and Durable Inhibition of the Human Protein Methyltransferase DOT1L.”	ki	0.0003	uM
5-[6-chloro-5-[2-chloro-5-[[4-(methylamino)pyrimidin-2-yl]amino]-1-benzothiophen-3-yl]-3-pyridinyl]-3,6-dimethylpyrimidin-4-one	1637654: Inhibition of DOT1L (2 to 416 residues) (unknown origin) using biotinylated nucleosomes as substrate preincubated for 30 mins followed by substrate addition in presence of [3H-Me]SAM by scintillation proximity assay	ki	0.0004	uM
1-[3-[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl-propan-2-ylamino]propyl]-3-(4-tert-butylphenyl)urea	1054112: Competitive inhibition of recombinant human DOT1L using adenosine/deazaadenosine as substrate and SAM cofactor	ki	0.0005	uM
1-N-[(S)-(3-chloro-2-fluorophenyl)-(3-fluoro-2-pyridinyl)methyl]-2-N-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylsulfonylbenzene-1,2-diamine	1611846: Inhibition of 0.05 nM DOT1L (2 to 416 residues) (unknown origin) using biotinylated nucleosome as substrate and [3H]SAM as co-factor preincubated for 30 mins followed by substrate and cofactor addition and measured after 180 mins by scintillation proximity assay	ic50	0.0006	uM
1-(4-tert-butylphenyl)-3-[3-[[(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(methylamino)purin-9-yl]oxolan-2-yl]methyl-propan-2-ylamino]propyl]urea	1054112: Competitive inhibition of recombinant human DOT1L using adenosine/deazaadenosine as substrate and SAM cofactor	ki	0.0008	uM
1-[3-[[(1R,2R,3S,4R)-4-(6-aminopurin-9-yl)-2,3-dihydroxycyclopentyl]methyl-propan-2-ylamino]propyl]-3-(4-tert-butylphenyl)urea	1054112: Competitive inhibition of recombinant human DOT1L using adenosine/deazaadenosine as substrate and SAM cofactor	ki	0.0011	uM
1-[3-[[(3R,4S,5R)-3-(6-aminopurin-9-yl)-4,5-dihydroxycyclopenten-1-yl]methyl-propan-2-ylamino]propyl]-3-(4-tert-butylphenyl)urea	1054112: Competitive inhibition of recombinant human DOT1L using adenosine/deazaadenosine as substrate and SAM cofactor	ki	0.0013	uM
2-[2-[[(S)-(3-chloro-2-fluorophenyl)-pyridin-2-ylmethyl]amino]-5-methylsulfonylanilino]pyrimidine-4-carboxamide	1611846: Inhibition of 0.05 nM DOT1L (2 to 416 residues) (unknown origin) using biotinylated nucleosome as substrate and [3H]SAM as co-factor preincubated for 30 mins followed by substrate and cofactor addition and measured after 180 mins by scintillation proximity assay	ic50	0.0021	uM
(1R,2S,3S,5R)-3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-[[[3-[2-(6-tert-butyl-1H-benzimidazol-2-yl)ethyl]cyclobutyl]-propan-2-ylamino]methyl]cyclopentane-1,2-diol	1905363: Inhibition of human DOT1L by hotspot PMT activity assay	ic50	0.0021	uM
1-[3-[[(2R,3S,4R,5R)-5-(4-amino-5-bromopyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxyoxolan-2-yl]methylamino]propyl]-3-(4-tert-butylphenyl)urea	2151438: Binding affinity to recombinant N-terminal DOT1L (1 to 420 residues) (unknown origin) expressed in Escherichia coli (DE3) assessed as dissociation constant by surface plasmon resonance assay	kd	0.0034	uM
2-[[1-(2-chlorophenyl)indol-6-yl]carbamoylamino]-N-[3-[[(3R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl]amino]propyl]acetamide	1437352: Inhibition of DOT1L (2 to 416 residues) (unknown origin) using biotinylated nucleosomes as substrate preincubated for 30 mins followed by substrate addition in presence of [3H-Me]SAM by scintillation proximity assay	ic50	0.0040	uM
2-[[1-(2-chlorophenyl)indol-6-yl]carbamoylamino]-N-[4-[[(3R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl]amino]butyl]acetamide	1437352: Inhibition of DOT1L (2 to 416 residues) (unknown origin) using biotinylated nucleosomes as substrate preincubated for 30 mins followed by substrate addition in presence of [3H-Me]SAM by scintillation proximity assay	ic50	0.0040	uM
1-[3-[[(3S,4R)-5-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxyoxolan-2-yl]methyl-methylamino]propyl]-3-(4-tert-butylphenyl)urea	1799816: Enzyme Assay from Article 10.1111/cbdd.12050: “Conformational Adaptation Drives Potent, Selective and Durable Inhibition of the Human Protein Methyltransferase DOT1L.”	ki	0.0040	uM
1-[3-[[(1S)-1-[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]ethyl]-propan-2-ylamino]propyl]-3-(4-tert-butylphenyl)urea	1479151: Inhibition of recombinant human N-terminal GST-tagged DOT1L (2 to 416 residues) expressed in Escherichia coli assessed as reduction in histone H3 lysine-N-methyltransferase activity using nucleosomes after 3 hrs in presence of SAM by AlphLisa assay	ic50	0.0063	uM
3-[6-chloro-5-[2-methyl-6-[[4-(methylamino)pyrimidin-2-yl]amino]indol-1-yl]-3-pyridinyl]-1,4-dimethylpyridin-2-one	1637654: Inhibition of DOT1L (2 to 416 residues) (unknown origin) using biotinylated nucleosomes as substrate preincubated for 30 mins followed by substrate addition in presence of [3H-Me]SAM by scintillation proximity assay	ic50	0.0100	uM
1-(4-tert-butylphenyl)-3-[3-[[(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(prop-2-enylamino)purin-9-yl]oxolan-2-yl]methyl-propan-2-ylamino]propyl]urea	702374: Inhibition of human recombinant DOT1L catalytic domain amino acid (1 to 472) using [3H]-SAM after 30 mins by scintillation counter	ki	0.0120	uM
(2S)-2-amino-4-[[(2S,3S,4R,5R)-5-(4-amino-5-cyanopyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxyoxolan-2-yl]methylsulfanyl]butanoic acid	1636909: Inhibition of human recombinant DOT1L (1 to 420 amino acids) expressed in Escherichia coli	ic50	0.0130	uM
(2S)-2-amino-4-[[(2R,3R,4S,5S)-5-(4-amino-5-cyanopyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxyoxolan-2-yl]methylsulfanyl]butanoic acid	1882358: Inhibition of DOT1L (unknown origin)	ic50	0.0130	uM
1-[3-[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl-methylamino]propyl]-3-(4-tert-butylphenyl)urea	1054112: Competitive inhibition of recombinant human DOT1L using adenosine/deazaadenosine as substrate and SAM cofactor	ki	0.0130	uM
1-[3-[[(3S,4R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl-methylamino]propyl]-3-(4-tert-butylphenyl)urea	1799816: Enzyme Assay from Article 10.1111/cbdd.12050: “Conformational Adaptation Drives Potent, Selective and Durable Inhibition of the Human Protein Methyltransferase DOT1L.”	ki	0.0130	uM
4-(N-(4-aminoquinazolin-6-yl)-2,6-dichloroanilino)-1-[1-(2-hydroxyethyl)imidazol-2-yl]but-2-yn-1-ol	1632641: Inhibition of human DOTL1 (2 to 416 residues)-mediated methylation of nucleosome preincubated for 30 mins followed by addition of S-[methyl-3H-] adenosyl-L-methionine and nucleosome measured after 180 mins by scintillation proximity assay	ic50	0.0140	uM
1-N-[(S)-(3-chloro-2-fluorophenyl)-(3-fluoro-2-pyridinyl)methyl]-4-methylsulfonyl-2-N-pyrimidin-2-ylbenzene-1,2-diamine	1611845: Inhibition of 0.5 nM DOT1L (2 to 416 residues) (unknown origin) using biotinylated nucleosome as substrate and [3H]SAM as co-factor preincubated for 30 mins followed by substrate and cofactor addition and measured after 90 mins by scintillation proximity assay	ic50	0.0160	uM
1-[3-[[(1R,2R,3S,4S)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,3-dihydroxycyclopentyl]methyl-methylamino]propyl]-3-(4-tert-butylphenyl)urea	1905363: Inhibition of human DOT1L by hotspot PMT activity assay	ic50	0.0190	uM
1-[1-(2-chlorophenyl)indol-6-yl]-3-[[2-[5-(2-chlorophenyl)tetrazol-1-yl]acetyl]amino]urea	1637654: Inhibition of DOT1L (2 to 416 residues) (unknown origin) using biotinylated nucleosomes as substrate preincubated for 30 mins followed by substrate addition in presence of [3H-Me]SAM by scintillation proximity assay	ic50	0.0200	uM
1-[3-[[(2R,3S,4R,5R)-5-[6-(benzylamino)purin-9-yl]-3,4-dihydroxyoxolan-2-yl]methyl-propan-2-ylamino]propyl]-3-(4-tert-butylphenyl)urea	702374: Inhibition of human recombinant DOT1L catalytic domain amino acid (1 to 472) using [3H]-SAM after 30 mins by scintillation counter	ki	0.0220	uM
(2S)-N-[(2S)-1-[[(2S)-3-amino-1-[[(2S)-1-[(2S)-2-[1-(cyclohexylmethyl)-4-phenylimidazol-2-yl]pyrrolidin-1-yl]-3-cyclopentyl-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-1-(4-methylpentanoyl)pyrrolidine-2-carboxamide	2120624: Binding affinity to DOT1L (unknown origin) assessed as inhibition constant	ki	0.0230	uM
1-[3-[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl-propan-2-ylamino]propyl]-3-(4-methylphenyl)urea	2151438: Binding affinity to recombinant N-terminal DOT1L (1 to 420 residues) (unknown origin) expressed in Escherichia coli (DE3) assessed as dissociation constant by surface plasmon resonance assay	kd	0.0269	uM
1-[3-[[(2R,3S,4R,5R)-5-(4-amino-5-chloropyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxyoxolan-2-yl]methyl-propan-2-ylamino]propyl]-3-(4-tert-butylphenyl)urea	1636919: Inhibition of human 6His-tagged DOT1L (1 to 420 residues) measured after 30 mins by AlphaScreen binding assay	ic50	0.0282	uM
(2S)-2-amino-5-[[(2S,3R,4S,5S)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl-(2-iodoethyl)amino]pentanoic acid	1882358: Inhibition of DOT1L (unknown origin)	ic50	0.0380	uM
(2S)-2-amino-4-[[(2S,3S,4R,5R)-5-(4-amino-5-bromopyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxyoxolan-2-yl]methylsulfanyl]butanoic acid	738916: Competitive inhibition of human recombinant DOT1L (1 to 420 amino acid residues) overexpressed in Escherichia coli BL21 (DE3) using [3H]-SAM as substrate assessed as inhibition of nucleosome methylation incubated for 30 mins prior to substrate addition measured after 1 hr by scintillation counting analysis	ki	0.0380	uM
(2S)-2-amino-5-[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl-(2-iodoethyl)amino]pentanoic acid	1054112: Competitive inhibition of recombinant human DOT1L using adenosine/deazaadenosine as substrate and SAM cofactor	ic50	0.0380	uM
6-N-(2,6-dichlorophenyl)-6-N-[3-(5-methyl-2-pyridinyl)prop-2-ynyl]quinazoline-4,6-diamine	1632641: Inhibition of human DOTL1 (2 to 416 residues)-mediated methylation of nucleosome preincubated for 30 mins followed by addition of S-[methyl-3H-] adenosyl-L-methionine and nucleosome measured after 180 mins by scintillation proximity assay	ic50	0.0470	uM
1-[3-[[(2S,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methylsulfanyl]propyl]-3-[4-(trifluoromethyl)phenyl]urea	1054112: Competitive inhibition of recombinant human DOT1L using adenosine/deazaadenosine as substrate and SAM cofactor	ki	0.0580	uM
1-[3-[[(2S,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methylsulfanyl]propyl]-3-(4-tert-butylphenyl)urea	1054112: Competitive inhibition of recombinant human DOT1L using adenosine/deazaadenosine as substrate and SAM cofactor	ki	0.0700	uM
1-(4-tert-butylphenyl)-3-[3-[[(2S,3S,4R,5R)-3,4-dihydroxy-5-[6-(methylamino)purin-9-yl]oxolan-2-yl]methylsulfanyl]propyl]urea	702374: Inhibition of human recombinant DOT1L catalytic domain amino acid (1 to 472) using [3H]-SAM after 30 mins by scintillation counter	ki	0.0700	uM
(2S)-2-amino-4-[[(2R,3R,4S,5S)-5-(4-amino-5-bromopyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxyoxolan-2-yl]methylsulfanyl]butanoic acid	1882358: Inhibition of DOT1L (unknown origin)	ic50	0.0770	uM
(1S,2R,3R,5S)-3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-[[[3-[2-(6-tert-butyl-1H-benzimidazol-2-yl)ethyl]cyclobutyl]-propan-2-ylamino]methyl]cyclopentane-1,2-diol	1905363: Inhibition of human DOT1L by hotspot PMT activity assay	ic50	0.0800	uM
1-[3-[[(2S,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methylsulfanyl]propyl]-3-[3,5-bis(trifluoromethyl)phenyl]urea	702374: Inhibition of human recombinant DOT1L catalytic domain amino acid (1 to 472) using [3H]-SAM after 30 mins by scintillation counter	ki	0.0800	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, affects splicing, decreases expression, increases expression	4
Valproic Acid	affects cotreatment, decreases expression, increases methylation	3
Air Pollutants	affects expression, increases abundance, increases expression	2
Cadmium	increases expression, decreases reaction, increases abundance, increases palmitoylation	2
Cisplatin	affects cotreatment, decreases expression	2
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, increases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
Batroxase, Bothrops atrox	increases expression	1
bisphenol F	increases methylation, affects cotreatment	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
titanium dioxide	decreases methylation	1
trichostatin A	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
coumarin	decreases phosphorylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
oleacein	decreases activity	1
EPZ004777	affects binding, decreases activity	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Arsenic	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Caffeine	affects phosphorylation	1
Estradiol	increases expression	1
Ozone	affects expression, increases abundance	1

ChEMBL screening assays

236 unique, capped per target: 235 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1804755	Binding	Inhibition of DOTL1-mediated methylation of nucleosome at 100 uM after 90 mins by scintillation counting in presence of S-adenosyl-l-[methyl-3H]methionine	Novel 3,5-bis(bromohydroxybenzylidene)piperidin-4-ones as coactivator-associated arginine methyltransferase 1 inhibitors: enzyme selectivity and cellular activity. — J Med Chem
CHEMBL4416351	ADMET	Inhibition of human DOT1L expressed in Escherichia coli assessed as reduction in methylated polynucleosome level using polynucleosome as substrate in presence of [3H] SAM incubated for 15 mins by scintillation counting	High-Affinity Alkynyl Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT). — J Med Chem

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8EU	Abcam HCT 116 DOT1L KO	Cancer cell line	Male
CVCL_B8UY	Abcam MCF-7 DOT1L KO	Cancer cell line	Female
CVCL_B9H2	Abcam A-549 DOT1L KO	Cancer cell line	Male
CVCL_SL08	HAP1 DOT1L (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
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