KMT2A

Summary

KMT2A (lysine methyltransferase 2A, HGNC:7132) is a protein-coding gene on chromosome 11q23.3, encoding Histone-lysine N-methyltransferase 2A (Q03164). Histone methyltransferase that plays an essential role in early development and hematopoiesis. In precision oncology, KMT2C Mutation OR KMT2A Mutation confers sensitivity to Immunotherapy in Cancer (CIViC Level B). It is a selective cancer dependency (DepMap: 11.4% of cell lines) and haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a transcriptional coactivator that plays an essential role in regulating gene expression during early development and hematopoiesis. The encoded protein contains multiple conserved functional domains. One of these domains, the SET domain, is responsible for its histone H3 lysine 4 (H3K4) methyltransferase activity which mediates chromatin modifications associated with epigenetic transcriptional activation. This protein is processed by the enzyme Taspase 1 into two fragments, MLL-C and MLL-N. These fragments reassociate and further assemble into different multiprotein complexes that regulate the transcription of specific target genes, including many of the HOX genes. Multiple chromosomal translocations involving this gene are the cause of certain acute lymphoid leukemias and acute myeloid leukemias. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 4297 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Wiedemann-Steiner syndrome (Definitive, ClinGen)
• GWAS associations: 6
• Clinical variants (ClinVar): 3,747 total — 360 pathogenic, 147 likely-pathogenic
• Phenotypes (HPO): 104
• Druggable target: yes — 535 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 9 cancer types
• Cancer dependency (DepMap): dependent in 11.4% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 81 downstream targets (CollecTRI)
• MANE Select transcript: NM_001197104

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7132
Approved symbol	KMT2A
Name	lysine methyltransferase 2A
Location	11q23.3
Locus type	gene with protein product
Status	Approved
Aliases	TRX1, HRX, ALL-1, HTRX1, CXXC7, MLL1A, MLL1, ALL1, HTRX
Ensembl gene	ENSG00000118058
Ensembl biotype	protein_coding
OMIM	159555
Entrez	4297

Gene structure

Transcript identifiers

Ensembl transcripts: 35 — 19 protein_coding, 9 retained_intron, 5 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000389506, ENST00000392873, ENST00000420751, ENST00000525408, ENST00000527839, ENST00000527869, ENST00000528278, ENST00000529852, ENST00000531904, ENST00000532204, ENST00000533790, ENST00000534085, ENST00000534358, ENST00000534678, ENST00000647638, ENST00000648029, ENST00000648565, ENST00000648910, ENST00000649410, ENST00000649666, ENST00000649690, ENST00000649699, ENST00000649878, ENST00000685397, ENST00000685498, ENST00000685719, ENST00000686370, ENST00000686588, ENST00000688355, ENST00000689424, ENST00000691002, ENST00000691053, ENST00000693536, ENST00000710560, ENST00000926390

RefSeq mRNA: 3 — MANE Select: NM_001197104 NM_001197104, NM_001412597, NM_005933

CCDS: CCDS31686, CCDS55791

Canonical transcript exons

ENST00000534358 — 36 exons

Exon	Start	End
ENSE00002436646	118480174	118480238
ENSE00002455788	118481715	118482092
ENSE00002463526	118468775	118468844
ENSE00002501544	118477967	118478201
ENSE00002528798	118482422	118482495
ENSE00002704839	118471662	118474315
ENSE00002714149	118476805	118476982
ENSE00003790034	118484183	118484314
ENSE00003838139	118436492	118436944
ENSE00004012346	118484862	118484975
ENSE00004012347	118491196	118491318
ENSE00004012348	118490129	118490249
ENSE00004012349	118495700	118495893
ENSE00004012350	118499835	118499913
ENSE00004012351	118500987	118501147
ENSE00004012352	118499303	118499420
ENSE00004012353	118494694	118494767
ENSE00004012354	118509948	118510118
ENSE00004012355	118488614	118488760
ENSE00004012356	118521288	118521417
ENSE00004012357	118519618	118519792
ENSE00004012358	118498370	118498528
ENSE00004012359	118521897	118526832
ENSE00004012360	118489792	118489887
ENSE00004012361	118520802	118520885
ENSE00004012363	118507529	118507609
ENSE00004012364	118493057	118493230
ENSE00004012365	118509136	118509200
ENSE00004012366	118511951	118512025
ENSE00004012367	118497936	118498073
ENSE00004012368	118502398	118506646
ENSE00004012369	118519957	118520064
ENSE00004012370	118491744	118491928
ENSE00004012371	118494288	118494398
ENSE00004012372	118501672	118501857
ENSE00004012373	118496261	118496367

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 96.53.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 35.9156 / max 403.3496, expressed in 1810 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
117003	35.9156	1810

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	96.53	gold quality
colonic epithelium	UBERON:0000397	96.34	gold quality
sural nerve	UBERON:0015488	95.64	gold quality
cortical plate	UBERON:0005343	95.16	gold quality
ganglionic eminence	UBERON:0004023	94.97	gold quality
calcaneal tendon	UBERON:0003701	94.37	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.92	gold quality
bone marrow cell	CL:0002092	93.40	gold quality
cerebellar vermis	UBERON:0004720	93.23	gold quality
lateral nuclear group of thalamus	UBERON:0002736	93.17	gold quality
lateral globus pallidus	UBERON:0002476	92.78	gold quality
middle temporal gyrus	UBERON:0002771	92.69	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	92.63	gold quality
cranial nerve II	UBERON:0000941	92.40	gold quality
substantia nigra pars reticulata	UBERON:0001966	92.13	gold quality
inferior vagus X ganglion	UBERON:0005363	92.08	gold quality
superior vestibular nucleus	UBERON:0007227	92.04	gold quality
corpus callosum	UBERON:0002336	91.98	gold quality
cardia of stomach	UBERON:0001162	91.95	gold quality
nipple	UBERON:0002030	91.95	gold quality
tonsil	UBERON:0002372	91.92	gold quality
medulla oblongata	UBERON:0001896	91.84	gold quality
Brodmann (1909) area 46	UBERON:0006483	91.72	gold quality
inferior olivary complex	UBERON:0002127	91.66	gold quality
saphenous vein	UBERON:0007318	91.56	gold quality
cerebellum	UBERON:0002037	91.49	gold quality
ventral tegmental area	UBERON:0002691	91.40	gold quality
subthalamic nucleus	UBERON:0001906	91.30	gold quality
parietal lobe	UBERON:0001872	91.27	gold quality
pylorus	UBERON:0001166	91.22	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-83139	no	719.95
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

81 targets.

Target	Regulation
ABCB1	Unknown
ABCC3
AFF1
AKT1
ANKRD2
APC
ASB2
ASXL1
ASXL2
ATM
AVP
BMI1
BTRC
CBX5
CCK
CCNA2
CD34
CD74
CDKN1B	Activation
CDKN2A
CFC1
CHD1
CHD8
CIITA
DACH1
DLX2	Activation
ELL2
EXOSC1
FGF2
FGFR1

Upstream regulators (CollecTRI, top): CREB1, KAT6A, KMT2A, NFKB, RELA, SOX4, SP1

miRNA regulators (miRDB)

354 targeting KMT2A, 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-4262	100.00	73.26	3931
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-190A-3P	100.00	80.35	5520
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-6798-5P	100.00	65.77	699
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-181A-5P	99.99	72.96	2995

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 11.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Nine (22.5%) of 40 patients exhibited MLL rearrangements. Three (33.3%) of these nine patients had granulocytic sarcoma and were younger than 12 months of age. (PMID:11733351)
• SEPTIN6, a human homologue to mouse Septin6, is fused to MLL in infant acute myeloid leukemia with complex chromosomal abnormalities involving 11q23 and Xq24. (PMID:11809673)
• An MLL rearrangement evolving as a secondary abnormality within a preexisting leukemic clone has been reported in a case of adult acute myeloid leukemia. (PMID:11921290)
• MLL-AF4 fusion gene rearrangements occurs between chromosome 4 and 11 in pre B-cell lymphoblastic leukemia (PMID:11943339)
• MLL amplification in myeloid malignancies: clinical, molecular, and cytogenetic findings (PMID:12034519)
• Fusion of MLL and MSF in adult de novo acute myelomonocytic leukemia (M4) with t(11;17)(q23;q25). (PMID:12095151)
• MLL-SEPTIN6 fusion recurs in novel translocation of chromosomes 3, X, and 11 in infant acute myelomonocytic leukaemia and in t(X;11) in infant acute myeloid leukaemia (PMID:12096348)
• FISH analysis in infant AML-M5 showed a complex rearrangement between chromosomes 10 and 11, disrupting the MLL gene, a paracentric inversion of the 11q13-q23 fragment translocated to 10p12. AF10 was the fusion partner gene of MLL in this rearrangement. (PMID:12127405)
• The correlation between infant leukemia and in utero exposure to topoisomerase II (topo-II) inhibitor has been clarified. in vitro effect of etoposide on cleavage of the MLL gene in cord and peripheral blood mononuclear cells (MNCs). (PMID:12138900)
• the MLL-AFX fusion protein transforms myeloid progenitors and interferes with forkhead protein function (PMID:12192052)
• Fusion of MLL to one of the AF4 family members (e.g., LAF4) may determine a proB-cell phenotype in infant leukemia. (PMID:12203795)
• MLL is proteolytically processed into 2 fragments with opposite transcriptional properties (PMID:12393701)
• A novel chromosomal inversion at 11q23 in acute myeloid leukemia fuses the MLL gene to the CALM gene. (PMID:12461747)
• This paper demonstrates that full length precursor MLL undergoes site-specific proteolysis to generate a heterodimeric complex consisting of N-terminal 320 kD and C-terminal 180kD of MLL. (PMID:12482972)
• we report that MLL is normally cleaved at two conserved sites (D/GADD and D/GVDD). MLL cleavage generates N-terminal p320 (N320) and C-terminal p180 (C180) fragments, which form a stable complex that localizes to a subnuclear compartment. (PMID:12482972)
• t(10;11)(p11.2;q23) involving this and ABI-1 genes is associated with congenital acute monocytic leukemia (PMID:12547160)
• myeloid gene dysregulation is dispensable in leukemic transformation mediated by MLL fusion proteins; dysregulation of HOX gene family members is implicated as a dominant mechanism of leukemic transformation induced by chimeric MLL oncogenes (PMID:12637319)
• demonstrated that TET1 is fused to MLL in a case of pediatric acute myeloid leukemia containing the t(10;11)(q22;q23) (PMID:12646957)
• Tandem duplication of the MLL gene may occur in AML with a partial 11q trisomy. Thus, systematic screening of this molecular defect should be performed in patients with unbalanced translocations involving 11q22 approximately q23–>qter (PMID:12660026)
• SWI/SNF complexes show considerable heterogeneity, and one or more may be involved in the etiology of leukemia by cooperating with MLL fusion proteins. (PMID:12665591)
• polymorphism within the MLL BCR has only a suggestive association with t-AML development. (PMID:12665971)
• MLL-CBL fusion was the result of an interstitial deletion in patients with de novo acute myeloid leukemia (FAB-M1). (PMID:12696071)
• loss of heterozygosity in the MLL gene in childhood ALL (PMID:12732503)
• There is fusion of an AF4-related gene, LAF4, to this gene in childhood acute lymphoblastic leukemia with t(2;11)(q11;q23). (PMID:12743608)
• Histone deacetylase 1 interacts with the MLL repression domain, partially mediating its activity; binding of Cyp33 to the adjacent MLLPolycomb group proteins HPC2 & BMI-1 & the corepressor C-terminal-binding protein also bind the MLL repression domain. (PMID:12829790)
• findings confirm the MLL gene as a prominent target of 11q23 amplification and provide further evidence for an etiologic role for MLL gain of function in myeloid malignancies (PMID:12946992)
• FLT3-D835/I836 mutations are one of the second genetic events in infant ALL with MLL rearrangements or pediatric ALL with hyperdiploidy (PMID:14504097)
• new mechanism for MLL-EEN-mediated leukemogenesis in which MLL-EEN interferes with the Ras-suppressing activities of EBP through direct interaction. (PMID:14551139)
• lack of HOX gene expression in acute lymphoblastic leukemia B-cells was not due to a nonfunctional MLL/AF4 (PMID:14562113)
• Involvement of the MLL gene located at chromosome region 11q23 is a frequent occurrence in both acute myelocytic leukemia and acute lymphoblastic leukemia. (PMID:14580777)
• This paper identifies the conserved protease, Taspase1, responsible for MLL proteolysis. (PMID:14636557)
• Review. The normal MLL gene plays a key role in developmental regulation of gene expression (including HOX genes), & in leukemia this function is subverted by breakage, recombination, and chimeric fusion with one of 40 or more alternative partner genes. (PMID:14704031)
• GPHN as an MLL-GPHN chimera is able to transform hematopoietic progenitors; a tubulin-binding domain of GPHN is necessary and sufficient for this activity and also confers oligomerization capacity on MLL protein, which may contribute to leukemogenesis (PMID:14751928)
• the cell cycle control exerted by MLL-AF4 may be responsible of resistance to cell-death promoting stimuli in leukemia carrying the t(4;11) translocation. (PMID:14990976)
• Extending the repertoire of the mixed-lineage leukemia gene MLL in leukemogenesis. Review. (PMID:15132992)
• suggest that MLL aberrations may regulate MEIS1 and HOXA9 gene expression in ALL-derived cell lines, while AML-derived cell lines express these genes independently of the MLL status (PMID:15160920)
• MLL associates with a cohort of proteins shared with the yeast and human SET1 histone methyltransferase complexes; studies link menin with the MLL histone methyltransferase machinery, with implications for Hox gene expression in leukemia pathogenesis (PMID:15199122)
• role of interaction with SIAH1 and SIAH2 proteins in t(4,11) pathobiology (PMID:15221006)
• the CXXC DNA binding domain has a critical role in MLL-associated oncogenesis, most likely via epigenetic recognition of CpG DNA sites within the regulatory elements of target genes (PMID:15542854)
• Some leukemic patients are inherently more susceptible to the genotoxic effect of topo 2 inhibitors. The degree and persistence of MLL cleavage may identify patients at risk. (PMID:15592432)

Cross-species orthologs

20 orthologs

Organism	Symbol	Gene ID
mus_musculus	Kmt2a	ENSMUSG00000002028
rattus_norvegicus	Kmt2a	ENSRNOG00000015133
drosophila_melanogaster	ash1	FBGN0005386
drosophila_melanogaster	trr	FBGN0023518
drosophila_melanogaster	Set2	FBGN0030486
drosophila_melanogaster	CG4565	FBGN0037841
drosophila_melanogaster	G9a	FBGN0040372
drosophila_melanogaster	egg	FBGN0086908
caenorhabditis_elegans	set-32	WBGENE00008062
caenorhabditis_elegans		WBGENE00008206
caenorhabditis_elegans		WBGENE00008527
caenorhabditis_elegans		WBGENE00011729
caenorhabditis_elegans	met-1	WBGENE00016603
caenorhabditis_elegans		WBGENE00018023
caenorhabditis_elegans		WBGENE00019584
caenorhabditis_elegans		WBGENE00019690
caenorhabditis_elegans		WBGENE00019883
caenorhabditis_elegans		WBGENE00020006
caenorhabditis_elegans		WBGENE00020919
caenorhabditis_elegans		WBGENE00021282

Paralogs (19): KMT2C (ENSG00000055609), SETD1A (ENSG00000099381), SUV39H1 (ENSG00000101945), EZH2 (ENSG00000106462), EZH1 (ENSG00000108799), NSD2 (ENSG00000109685), ASH1L (ENSG00000116539), SETDB2 (ENSG00000136169), SETD1B (ENSG00000139718), SETDB1 (ENSG00000143379), NSD3 (ENSG00000147548), SETBP1 (ENSG00000152217), SUV39H2 (ENSG00000152455), NSD1 (ENSG00000165671), KMT2D (ENSG00000167548), EHMT1 (ENSG00000181090), SETD2 (ENSG00000181555), EHMT2 (ENSG00000204371), KMT2B (ENSG00000272333)

Protein

Protein identifiers

Histone-lysine N-methyltransferase 2A — Q03164 (reviewed: Q03164)

Alternative names: ALL-1, CXXC-type zinc finger protein 7, Cysteine methyltransferase KMT2A, Myeloid/lymphoid or mixed-lineage leukemia, Myeloid/lymphoid or mixed-lineage leukemia protein 1, Trithorax-like protein, Zinc finger protein HRX

All UniProt accessions (20): Q03164, A0A3B3ISN4, A0A3B3ITT0, A0A3B3ITT7, A0A8I5KQ03, A0A8I5KQV5, A0A8I5KRT6, A0A8I5KRW5, A0A8I5KTQ4, A0A8I5KVD4, A0A8I5KVV7, A0A8I5KW84, A0A8I5KXR3, A0A8I5KY70, A0A8I5QJJ1, A0AA34QVI8, E9PR05, H0YEU4, H7C5V8, H7C5W4

UniProt curated annotations — full annotation on UniProt →

Function. Histone methyltransferase that plays an essential role in early development and hematopoiesis. Catalytic subunit of the MLL1/MLL complex, a multiprotein complex that mediates both methylation of ‘Lys-4’ of histone H3 (H3K4me) complex and acetylation of ‘Lys-16’ of histone H4 (H4K16ac). Catalyzes methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of ‘Lys-4’ of histone H3 (H3K4) via a non-processive mechanism. Part of chromatin remodeling machinery predominantly forms H3K4me1 and H3K4me2 methylation marks at active chromatin sites where transcription and DNA repair take place. Has weak methyltransferase activity by itself, and requires other component of the MLL1/MLL complex to obtain full methyltransferase activity. Has no activity toward histone H3 phosphorylated on ‘Thr-3’, less activity toward H3 dimethylated on ‘Arg-8’ or ‘Lys-9’, while it has higher activity toward H3 acetylated on ‘Lys-9’. Binds to unmethylated CpG elements in the promoter of target genes and helps maintain them in the nonmethylated state. Required for transcriptional activation of HOXA9. Promotes PPP1R15A-induced apoptosis. Plays a critical role in the control of circadian gene expression and is essential for the transcriptional activation mediated by the CLOCK-BMAL1 heterodimer. Establishes a permissive chromatin state for circadian transcription by mediating a rhythmic methylation of ‘Lys-4’ of histone H3 (H3K4me) and this histone modification directs the circadian acetylation at H3K9 and H3K14 allowing the recruitment of CLOCK-BMAL1 to chromatin. Also has auto-methylation activity on Cys-3882 in absence of histone H3 substrate.

Subunit / interactions. MLL cleavage product N320 heterodimerizes with MLL cleavage product C180 (via SET and FYRC domains). Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1/HCF1, HCFC2, WDR5, DPY30 and RBBP5, as well as the facultative components BACC1, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MEN1, MGA, KAT8/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10. Forms a core complex with the evolutionary conserved subcomplex WRAD composed of WDR5, RBBP5, ASH2L/ASH2 and DPY30 subunits; WRAD differentially stimulates the methyltransferase activity. Interacts (via WIN motif) with WDR5; the interaction is direct. Interaction with WDR5 is required for stable interaction with ASH2L and RBBP5, and thereby also for optimal histone methyltransferase activity. Interacts with KAT8/MOF; the interaction is direct. Interacts with SBF1 and PPP1R15A. Interacts with ZNF335. Interacts with CLOCK and BMAL1 in a circadian manner. Interacts with PPIE; this results in decreased histone H3 methyltransferase activity. Interacts with CREBBP. Interacts with the WRAD complex composed of WDR5, RBBP5, ASH2L and DPY30. Interacts (via MBM motif) with MEN1. Interacts (via IBM motifs) with PSIP1 (via IBD domain) with moderate affinity whereas the KMT2A-MEN1 complex interacts with a greater affinity; MEN1 enhances interaction of KMT2A with PSIP1. Phosphorylation increases its affinity for PSIP1. Forms a complex with CREBBP and CREB1. (Microbial infection) Interacts with herpes virus 8/HHV-8 protein LANA1; this interaction regulates the MLL1 histone methyltransferase activity on viral DNA.

Subcellular location. Nucleus Nucleus Nucleus.

Tissue specificity. Heart, lung, brain and T- and B-lymphocytes.

Post-translational modifications. Proteolytic cleavage by TASP1 generates MLL cleavage product N320 and MLL cleavage product C180, which reassemble through a non-covalent association. 2 cleavage sites exist, cleavage site 1 (CS1) and cleavage site 2 (CS2), to generate MLL cleavage products N320 and C180. CS2 is the major site. Phosphorylation increases its interaction with PSIP1. Auto-methylated at Cys-3882: auto-methylation is inhibited by the WRAD complex and unmodified histone H3.

Disease relevance. Wiedemann-Steiner syndrome (WDSTS) [MIM:605130] A syndrome characterized by hairy elbows (hypertrichosis cubiti), intellectual disability, a distinctive facial appearance, and short stature. Facial characteristics include long eyelashes, thick or arched eyebrows with a lateral flare, and downslanting and vertically narrow palpebral fissures. The disease is caused by variants affecting the gene represented in this entry. Chromosomal aberrations involving KMT2A are a cause of acute leukemias. Translocation t(1;11)(q21;q23) with MLLT11/AF1Q; translocation t(3;11)(p21;q23) with NCKIPSD/AF3p21; translocation t(3,11)(q25,q23) with GMPS; translocation t(4;11)(q21;q23) with AFF1/MLLT2/AF4; insertion ins(5;11)(q31;q13q23) with AFF4/AF5Q31; translocation t(5;11)(q12;q23) with AF5-alpha/CENPK; translocation t(6;11)(q27;q23) with AFDN; translocation t(9;11)(p22;q23) with MLLT3/AF9; translocation t(10;11)(p11.2;q23) with ABI1; translocation t(10;11)(p12;q23) with MLLT10/AF10; t(11;15)(q23;q14) with KNL1 and ZFYVE19; translocation t(11;17)(q23;q21) with MLLT6/AF17; translocation t(11;19)(q23;p13.3) with ELL; translocation t(11;19)(q23;p13.3) with MLLT1/ENL; translocation t(11;19)(q23;p23) with GAS7; translocation t(X;11)(q13;q23) with FOXO4/AFX1. Translocation t(3;11)(q28;q23) with LPP. Translocation t(10;11)(q22;q23) with TET1. Translocation t(9;11)(q34;q23) with DAB2IP. Translocation t(4;11)(p12;q23) with FRYL. Fusion proteins KMT2A-MLLT1, KMT2A-MLLT3 and KMT2A-ELL interact with PPP1R15A and, on the contrary to unfused KMT2A, inhibit PPP1R15A-induced apoptosis. Fusion protein KMT2A-MLLT3 interacts with MEN1 and PSIP1. A chromosomal aberration involving KMT2A may be a cause of chronic neutrophilic leukemia. Translocation t(4;11)(q21;q23) with SEPT11.

Domain organisation. The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors. The SET domain structure is atypical and is not in an optimal position to have methyltransferase activity. It requires other components of the MLL1/MLL complex, such as ASH2L or RBBP5, to order the active site and obtain optimal histone methyltransferase activity. The CXXC-type zinc finger binds to DNA sequence elements containing unnmethylated CpG dinucleotides. The third PHD-type zinc-finger binds both trimethylated histone H3K4me3 and PPIE; histone and PPIE bind to distinct surfaces. Nevertheless, PPIE binding and histone binding are mutually inhibitory. Isomerization of a peptidylproline bond in the linker between the third PHD-type zinc-finger and the bromo domain disrupts the interaction between the bromo domain and the third PHD-type zinc-finger, and thereby facilitates interaction with PPIE.

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

Isoforms (3)

UniProt ID	Names	Canonical?
Q03164-1	1	yes
Q03164-2	2, 14P-18B
Q03164-3	3

RefSeq proteins (3): NP_001184033, NP_001399526, NP_005924 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001214	SET_dom	Domain
IPR001487	Bromodomain	Domain
IPR001965	Znf_PHD	Domain
IPR002857	Znf_CXXC	Domain
IPR003616	Post-SET_dom	Domain
IPR003888	FYrich_N	Conserved_site
IPR003889	FYrich_C	Conserved_site
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR016569	MeTrfase_trithorax	Family
IPR019787	Znf_PHD-finger	Domain
IPR034732	EPHD	Domain
IPR036427	Bromodomain-like_sf	Homologous_superfamily
IPR041958	KMT2A_ePHD	Domain
IPR042023	KMT2A_PHD1	Domain
IPR042025	KMT2A_PHD2	Domain
IPR044133	KMT2A_PHD3	Domain
IPR046341	SET_dom_sf	Homologous_superfamily
IPR047219	KMT2A_2B_SET	Domain

Pfam: PF00628, PF00856, PF02008, PF05964, PF05965, PF13771

Catalyzed reactions (Rhea), 3 shown:

• L-lysyl(4)-[histone H3] + S-adenosyl-L-methionine = N(6)-methyl-L-lysyl(4)-[histone H3] + S-adenosyl-L-homocysteine + H(+) (RHEA:60264)
• N(6)-methyl-L-lysyl(4)-[histone H3] + S-adenosyl-L-methionine = N(6),N(6)-dimethyl-L-lysyl(4)-[histone H3] + S-adenosyl-L-homocysteine + H(+) (RHEA:60268)
• L-cysteinyl-[protein] + S-adenosyl-L-methionine = S-methyl-L-cysteinyl-[protein] + S-adenosyl-L-homocysteine + H(+) (RHEA:66544)

UniProt features (311 total): mutagenesis site 82, compositionally biased region 43, modified residue 33, region of interest 24, helix 23, strand 22, binding site 17, sequence conflict 16, site 10, sequence variant 9, turn 7, zinc finger region 6, domain 5, short sequence motif 5, chain 3, DNA-binding region 3, splice variant 2, cross-link 1

Structure

Experimental structures (PDB)

60 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
3EMH	X-RAY DIFFRACTION	1.37
9C4T	X-RAY DIFFRACTION	1.46
9C4V	X-RAY DIFFRACTION	1.47
7S79	X-RAY DIFFRACTION	1.53
9C4S	X-RAY DIFFRACTION	1.54
4GQ6	X-RAY DIFFRACTION	1.55
7S7D	X-RAY DIFFRACTION	1.56
9C4U	X-RAY DIFFRACTION	1.57
7S8E	X-RAY DIFFRACTION	1.6
4ESG	X-RAY DIFFRACTION	1.7
3EG6	X-RAY DIFFRACTION	1.72
3LQH	X-RAY DIFFRACTION	1.72
7RZJ	X-RAY DIFFRACTION	1.8
7S8F	X-RAY DIFFRACTION	1.8
5F5E	X-RAY DIFFRACTION	1.8
7RZD	X-RAY DIFFRACTION	1.82
3LQJ	X-RAY DIFFRACTION	1.9
5F6L	X-RAY DIFFRACTION	1.9
3LQI	X-RAY DIFFRACTION	1.92
6U9N	X-RAY DIFFRACTION	1.95
2W5Y	X-RAY DIFFRACTION	2
6U9K	X-RAY DIFFRACTION	2
5SVH	X-RAY DIFFRACTION	2.05
6U9M	X-RAY DIFFRACTION	2.05
6U9R	X-RAY DIFFRACTION	2.1
7S8A	X-RAY DIFFRACTION	2.1
7W67	X-RAY DIFFRACTION	2.19
2W5Z	X-RAY DIFFRACTION	2.2
7W6A	X-RAY DIFFRACTION	2.21
3P4F	X-RAY DIFFRACTION	2.35

Predicted structure (AlphaFold)

No AlphaFold model available for Q03164 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

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

Catalytic / active sites (10): 1334–1335 (breakpoint for translocation to form kmt2a-zfyve19 oncogene); 1362–1363 (breakpoint for translocation to form kmt2a-af3p21 and kmt2a-knl1 oncogenes); 1362–1363 (breakpoint for translocation to form kmt2a-cenpk oncogene); 1362 (breakpoint for translocation to form kmt2a-fryl fusion protein); 1406–1407 (breakpoint for translocation to form kmt2a-aff4 fusion protein); 1444–1445 (breakpoint for translocation to form kmt2a-gas7 oncogene); 1444–1445 (breakpoint for translocation to form kmt2a-lpp); 2666–2667 (cleavage; by tasp1, site 1); 2718–2719 (cleavage; by tasp1, site 2); 3765 (important for wdr5-recognition and binding)

Ligand- & substrate-binding residues (17): 3906–3907; 3909; 3957; 3958; 3959; 3964; 1155; 1158; 1161; 1167; 1170; 1173 …

Post-translational modifications (34): 136, 142, 153, 197, 239, 373, 518, 636, 680, 840, 926, 1056, 1130, 1235, 1837, 1845, 1858, 2098, 2147, 2151 …

Mutagenesis-validated functional residues (82):

Position	Phenotype
6	reduced interaction with men1.
7	reduced interaction with men1.
8	reduced interaction with men1.
9	loss of interaction with men1.
9	reduced interaction with men1.
10	reduced interaction with men1.
11	reduced interaction with men1.
12	reduced interaction with men1.
13	reduced interaction with men1.
24	reduced interaction with men1; when associated with e-25.
25	reduced interaction with men1; when associated with e-24.
129	weakly affects interaction with psip1 whereas significantly decreases interaction of kmt2a-men1 complex with psip1. redu
132	reduced interaction with psip1; when associated with a-133.
133	reduced interaction with psip1; when associated with a-129 or a-132.
136	phosphomimetic mutant. significant increase in interaction with psip1; when associated with d-142.
142	phosphomimetic mutant. significant increase in interaction with psip1; when associated with d-136.
144	loss of interaction with psip1; when associated with q-146 and a-148.
146	loss of interaction with psip1; when associated with q-144 and a-148.
148	reduced interaction with psip1. loss of interaction with psip1; when associated with a-149 or q-144 and q-146.
149	loss of interaction with psip1; when associated with a-148.
151	reduced interaction with psip1.
1150	impairs dna-binding.
1151	impairs dna-binding.
1153	no effect on stability or dna-binding.
1154	impairs dna-binding.

Function

Pathways and Gene Ontology

Reactome pathways

19 pathways

ID	Pathway
R-HSA-3214841	PKMTs methylate histone lysines
R-HSA-8936459	RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function
R-HSA-8939236	RUNX1 regulates transcription of genes involved in differentiation of HSCs
R-HSA-9616222	Transcriptional regulation of granulopoiesis
R-HSA-9772755	Formation of WDR5-containing histone-modifying complexes
R-HSA-9909649	Regulation of PD-L1(CD274) transcription
R-HSA-9931510	Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes
R-HSA-9931512	Phosphorylation of CLOCK, acetylation of BMAL1 (ARNTL) at target gene promoters
R-HSA-9931521	The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex
R-HSA-9976102	Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)
R-HSA-1266738	Developmental Biology
R-HSA-212165	Epigenetic regulation of gene expression
R-HSA-212436	Generic Transcription Pathway
R-HSA-3247509	Chromatin modifying enzymes
R-HSA-4839726	Chromatin organization
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8878171	Transcriptional regulation by RUNX1
R-HSA-9917777	Epigenetic regulation by WDR5-containing histone modifying complexes

MSigDB gene sets: 759 (showing top): GOBP_CIRCADIAN_RHYTHM, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_MEMBRANE_DEPOLARIZATION, GOBP_EMBRYONIC_HEMOPOIESIS, AAGCAAT_MIR137, GOBP_COGNITION, GOBP_BEHAVIOR, TGCGCANK_UNKNOWN, GCM_GSPT1, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_REGULATION_OF_NEURONAL_SYNAPTIC_PLASTICITY, GCANCTGNY_MYOD_Q6, GOBP_ASSOCIATIVE_LEARNING

GO Biological Process (32): apoptotic process (GO:0006915), visual learning (GO:0008542), post-embryonic development (GO:0009791), anterior/posterior pattern specification (GO:0009952), methylation (GO:0032259), circadian regulation of gene expression (GO:0032922), embryonic hemopoiesis (GO:0035162), exploration behavior (GO:0035640), response to potassium ion (GO:0035864), T-helper 2 cell differentiation (GO:0045064), transcription initiation-coupled chromatin remodeling (GO:0045815), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), fibroblast proliferation (GO:0048144), negative regulation of fibroblast proliferation (GO:0048147), regulation of short-term neuronal synaptic plasticity (GO:0048172), spleen development (GO:0048536), homeostasis of number of cells within a tissue (GO:0048873), membrane depolarization (GO:0051899), definitive hemopoiesis (GO:0060216), protein-containing complex assembly (GO:0065003), cellular response to transforming growth factor beta stimulus (GO:0071560), negative regulation of DNA methylation-dependent heterochromatin formation (GO:0090310), immune system process (GO:0002376), chromatin organization (GO:0006325), regulation of DNA-templated transcription (GO:0006355), response to light stimulus (GO:0009416), regulation of gene expression (GO:0010468), positive regulation of gene expression (GO:0010628), epigenetic regulation of gene expression (GO:0040029), rhythmic process (GO:0048511), cognition (GO:0050890)

GO Molecular Function (15): minor groove of adenine-thymine-rich DNA binding (GO:0003680), chromatin binding (GO:0003682), zinc ion binding (GO:0008270), histone H3K4 methyltransferase activity (GO:0042800), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), unmethylated CpG binding (GO:0045322), protein-cysteine methyltransferase activity (GO:0106363), histone H3K4 monomethyltransferase activity (GO:0140945), histone H3K4 trimethyltransferase activity (GO:0140999), DNA binding (GO:0003677), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), histone methyltransferase complex (GO:0035097), MLL1 complex (GO:0071339), MLL1/2 complex (GO:0044665)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Circadian clock	3
Transcriptional regulation by RUNX1	2
Gene expression (Transcription)	2
Chromatin modifying enzymes	1
Developmental Biology	1
Epigenetic regulation by WDR5-containing histone modifying complexes	1
Regulation of PD-L1(CD274) expression	1
Differentiation of T cells	1
RNA Polymerase II Transcription	1
Chromatin organization	1
Generic Transcription Pathway	1
Epigenetic regulation of gene expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
hemopoiesis	2
binding	2
histone H3K4 methyltransferase activity	2
cellular anatomical structure	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
visual behavior	1
associative learning	1
multicellular organism development	1
multicellular organismal process	1
regionalization	1
metabolic process	1
circadian rhythm	1
regulation of gene expression	1
embryonic organ development	1
behavior	1
response to metal ion	1
alpha-beta T cell activation involved in immune response	1
T cell differentiation involved in immune response	1
type 2 immune response	1
T-helper cell differentiation	1
transcription initiation at RNA polymerase II promoter	1
positive regulation of gene expression, epigenetic	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
cell population proliferation	1
negative regulation of cell population proliferation	1
fibroblast proliferation	1
regulation of fibroblast proliferation	1
regulation of neuronal synaptic plasticity	1
hematopoietic or lymphoid organ development	1
tissue homeostasis	1
homeostasis of number of cells	1
regulation of membrane potential	1
DNA secondary structure binding	1

Protein interactions and networks

STRING

3495 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KMT2A	MEN1	O00255	990
KMT2A	WDR5	P61964	978
KMT2A	AFF1	P51825	978
KMT2A	MLLT3	P42568	964
KMT2A	KMT2D	O14686	954
KMT2A	MLLT1	Q03111	948
KMT2A	ASH2L	Q9UBL3	925
KMT2A	RBBP5	Q15291	896
KMT2A	KMT2B	Q9UMN6	876
KMT2A	PHF8	Q9UPP1	861
KMT2A	MLLT11	Q13015	859
KMT2A	MLLT10	P55197	845
KMT2A	KMT2C	Q8NEZ4	839
KMT2A	PHF6	Q8IWS0	838
KMT2A	SETD1A	O15047	832

IntAct

241 interactions, top by confidence:

A	B	Type	Score
KMT2A	WDR5	psi-mi:“MI:0915”(physical association)	0.960
KMT2A	WDR5	psi-mi:“MI:0407”(direct interaction)	0.960
WDR5	KMT2A	psi-mi:“MI:0407”(direct interaction)	0.960
ASH2L	WDR5	psi-mi:“MI:0915”(physical association)	0.950
ASH2L	WDR5	psi-mi:“MI:0403”(colocalization)	0.950
KMT2A	RBBP5	psi-mi:“MI:0915”(physical association)	0.940
KMT2B	WDR5	psi-mi:“MI:0407”(direct interaction)	0.940
RBBP5	KMT2A	psi-mi:“MI:0914”(association)	0.940
RBBP5	KMT2A	psi-mi:“MI:0407”(direct interaction)	0.940
WDR5	KMT2D	psi-mi:“MI:0914”(association)	0.910
ASH2L	KMT2D	psi-mi:“MI:0914”(association)	0.890
RBBP5	KMT2D	psi-mi:“MI:0914”(association)	0.840
CSNK2A1	EIF3J	psi-mi:“MI:0914”(association)	0.810
CSNK2A2	EIF3J	psi-mi:“MI:0914”(association)	0.790
KMT2A	KMT2A	psi-mi:“MI:0407”(direct interaction)	0.730
KMT2A	KMT2A	psi-mi:“MI:0915”(physical association)	0.730
	KMT2A	psi-mi:“MI:0914”(association)	0.730
KMT2A		psi-mi:“MI:0914”(association)	0.730

BioGRID (578): PPIE (Two-hybrid), PPP1R15A (Two-hybrid), KMT2A (Two-hybrid), KMT2A (Co-localization), ASH2L (Affinity Capture-Western), RBBP5 (Affinity Capture-Western), WDR5 (Affinity Capture-Western), HCFC1 (Affinity Capture-Western), KMT2A (Reconstituted Complex), HIST1H3A (Biochemical Activity), KMT2A (Protein-peptide), WDR5 (Reconstituted Complex), HIST1H3A (Biochemical Activity), KMT2A (Affinity Capture-MS), KMT2A (Affinity Capture-MS)

ESM2 similar proteins: A2A884, F1QQA8, O08696, O43151, O94993, P08651, P09414, P15822, P17923, P21999, P31629, P55200, Q00900, Q01538, Q03164, Q03172, Q08050, Q08D57, Q12857, Q1LY77, Q2M1Z3, Q3UHF7, Q3UTJ2, Q498L0, Q499E5, Q5DTJ9, Q5SW79, Q5T1R4, Q5ZKH6, Q62255, Q62417, Q66J90, Q69Z38, Q6A065, Q86V15, Q8BG87, Q8C5W0, Q8CFC2, Q8CGW4, Q8CH77

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

9 interactions.

A	Effect	B	Mechanism
KMT2A	up-regulates	KAT8	binding
PAX7	up-regulates	KMT2A	binding
KMT2A	“form complex”	“MLL1 complex”	binding
ATR	up-regulates	KMT2A	phosphorylation
KMT2A	“up-regulates quantity by stabilization”	RUNX1	binding
MEN1	“up-regulates activity”	KMT2A	binding
KMT2A	up-regulates	Epigenetic_regulation
KMT2A	“up-regulates quantity by expression”	SPI1	methylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 145 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
Activation of BAD and translocation to mitochondria	6	41.9×	3e-07
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	37.0×	4e-07
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	37.0×	4e-07
Formation of WDR5-containing histone-modifying complexes	13	31.7×	5e-14
Activation of BH3-only proteins	6	27.3×	2e-06
RHO GTPases activate PKNs	7	20.4×	2e-06
FOXO-mediated transcription	6	18.5×	2e-05
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	9	16.3×	3e-07

GO biological processes:

GO term	Partners	Fold	FDR
transcription initiation-coupled chromatin remodeling	7	20.3×	1e-05
cellular response to UV	5	11.2×	4e-03
negative regulation of translation	7	10.4×	6e-04
positive regulation of transcription initiation by RNA polymerase II	5	10.3×	6e-03
cytoplasmic translation	7	9.8×	7e-04
nucleosome assembly	7	7.5×	3e-03
chromatin remodeling	13	7.2×	1e-05
intracellular protein localization	9	7.1×	6e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 9 cancer types — ACC, BLCA, ESCC, HCC, OVT, PAAD, PRAD, SIC, WDTC.

Clinical variants and AI predictions

ClinVar

3747 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	360
Likely pathogenic	147
Uncertain significance	1773
Likely benign	1085
Benign	96

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1031915	NM_001197104.2(KMT2A):c.1395_1396insG (p.Ser466fs)	Pathogenic
1065449	NM_001197104.2(KMT2A):c.7597del (p.Glu2533fs)	Pathogenic
1069875	NM_001197104.2(KMT2A):c.3926del (p.Pro1309fs)	Pathogenic
1072842	NM_001197104.2(KMT2A):c.2865del (p.Val956fs)	Pathogenic
1073103	NM_001197104.2(KMT2A):c.2629_2630del (p.Asp877fs)	Pathogenic
1075632	NM_001197104.2(KMT2A):c.3063_3085del (p.Arg1022fs)	Pathogenic
1098356	NM_001197104.2(KMT2A):c.2452A>T (p.Lys818Ter)	Pathogenic
1098361	NM_001197104.2(KMT2A):c.5935C>T (p.Arg1979Ter)	Pathogenic
1164060	NM_001197104.2(KMT2A):c.2483C>G (p.Ser828Ter)	Pathogenic
1172651	NM_001197104.2(KMT2A):c.10023dup (p.Ser3342fs)	Pathogenic
1174098	NM_001197104.2(KMT2A):c.5822del (p.Lys1941fs)	Pathogenic
1176918	NM_001197104.2(KMT2A):c.1704dup (p.Pro569fs)	Pathogenic
1176920	NM_001197104.2(KMT2A):c.2413C>T (p.Gln805Ter)	Pathogenic
1182117	NM_001197104.2(KMT2A):c.2629_2630dup (p.Asp877fs)	Pathogenic
1184000	NM_001197104.2(KMT2A):c.5256dup (p.Ala1753fs)	Pathogenic
1184107	NM_001197104.2(KMT2A):c.2388dup (p.Thr797fs)	Pathogenic
1184120	NM_001197104.2(KMT2A):c.9436C>T (p.Gln3146Ter)	Pathogenic
1184449	NM_001197104.2(KMT2A):c.2690C>G (p.Ser897Ter)	Pathogenic
1186022	NM_001197104.2(KMT2A):c.3563G>T (p.Cys1188Phe)	Pathogenic
1188831	NM_001197104.2(KMT2A):c.152_186del (p.Pro51fs)	Pathogenic
1191371	NM_001197104.2(KMT2A):c.1104_1114dup (p.Ala372fs)	Pathogenic
1197588	NM_001197104.2(KMT2A):c.2214_2218del (p.Arg738fs)	Pathogenic
1254470	NM_001197104.2(KMT2A):c.5572C>T (p.Arg1858Ter)	Pathogenic
1285418	NM_001197104.1:c.(4332+1_4333-1)_(6505+1_6506-1)del	Pathogenic
1320181	NM_001197104.2(KMT2A):c.731T>G (p.Leu244Ter)	Pathogenic
1320198	NM_001197104.2(KMT2A):c.3634+1G>A	Pathogenic
1328132	NM_001197104.2(KMT2A):c.3241C>T (p.Arg1081Ter)	Pathogenic
1330233	NM_001197104.2(KMT2A):c.7155del (p.His2385fs)	Pathogenic
1334474	NM_001197104.2(KMT2A):c.1274del (p.Pro425fs)	Pathogenic
1334646	NM_001197104.2(KMT2A):c.5455C>T (p.Gln1819Ter)	Pathogenic

SpliceAI

5021 predictions. Top by Δscore:

Variant	Effect	Δscore
11:118468774:GGAT:G	acceptor_gain	1.0000
11:118468840:TTCAG:T	donor_loss	1.0000
11:118468841:TCAG:T	donor_loss	1.0000
11:118468843:AGG:A	donor_loss	1.0000
11:118468844:GG:G	donor_loss	1.0000
11:118468845:GT:G	donor_loss	1.0000
11:118468846:T:G	donor_loss	1.0000
11:118476786:T:TA	acceptor_gain	1.0000
11:118476787:G:A	acceptor_gain	1.0000
11:118476800:TTCA:T	acceptor_loss	1.0000
11:118476802:CAG:C	acceptor_loss	1.0000
11:118476803:A:AG	acceptor_gain	1.0000
11:118476803:AG:A	acceptor_gain	1.0000
11:118476804:G:GT	acceptor_gain	1.0000
11:118476804:GG:G	acceptor_gain	1.0000
11:118476804:GGGT:G	acceptor_gain	1.0000
11:118476943:G:GT	donor_gain	1.0000
11:118476943:G:T	donor_gain	1.0000
11:118476979:GATG:G	donor_gain	1.0000
11:118476983:G:GG	donor_gain	1.0000
11:118476983:G:T	donor_loss	1.0000
11:118476984:T:A	donor_loss	1.0000
11:118477965:A:AG	acceptor_gain	1.0000
11:118477966:G:GT	acceptor_gain	1.0000
11:118477966:GA:G	acceptor_gain	1.0000
11:118477966:GAC:G	acceptor_gain	1.0000
11:118477966:GACA:G	acceptor_gain	1.0000
11:118477966:GACAA:G	acceptor_gain	1.0000
11:118478078:G:GT	donor_gain	1.0000
11:118478202:G:GG	donor_gain	1.0000

AlphaMissense

25892 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:118472283:T:C	L375P	1.000
11:118472397:T:A	V413D	1.000
11:118472400:T:A	V414D	1.000
11:118473014:T:A	W619R	1.000
11:118473014:T:C	W619R	1.000
11:118473263:T:C	F702L	1.000
11:118473264:T:C	F702S	1.000
11:118473265:T:A	F702L	1.000
11:118473265:T:G	F702L	1.000
11:118474236:T:C	L1026P	1.000
11:118474239:T:C	L1027P	1.000
11:118474247:G:C	A1030P	1.000
11:118474248:C:A	A1030D	1.000
11:118476851:T:A	I1068N	1.000
11:118476851:T:C	I1068T	1.000
11:118476851:T:G	I1068S	1.000
11:118476853:A:G	K1069E	1.000
11:118476854:A:T	K1069I	1.000
11:118476855:A:C	K1069N	1.000
11:118476855:A:T	K1069N	1.000
11:118476856:C:G	H1070D	1.000
11:118476857:A:G	H1070R	1.000
11:118476858:T:A	H1070Q	1.000
11:118476858:T:G	H1070Q	1.000
11:118476860:T:A	V1071D	1.000
11:118476862:T:A	C1072S	1.000
11:118476862:T:C	C1072R	1.000
11:118476863:G:A	C1072Y	1.000
11:118476863:G:C	C1072S	1.000
11:118476863:G:T	C1072F	1.000

dbSNP variants (sampled 300 via entrez): RS1000009405 (11:118499978 G>C), RS1000118089 (11:118451143 T>C), RS1000177972 (11:118454687 T>C), RS1000317429 (11:118511836 G>A,C), RS1000423457 (11:118474369 T>A,C), RS1000487221 (11:118479958 A>G), RS1000576457 (11:118435862 A>T), RS1000595829 (11:118487763 A>G), RS1000628649 (11:118435588 T>A), RS1000769241 (11:118495612 G>A), RS1000838378 (11:118463373 G>A,C), RS1000847634 (11:118457812 G>T), RS1000870738 (11:118463127 T>A), RS1000889623 (11:118517943 G>A), RS1000988402 (11:118525894 G>T)

Disease associations

OMIM: gene MIM:159555 | disease phenotypes: MIM:605130, MIM:122470, MIM:147920, MIM:180850

GenCC curated gene-disease

Disease	Classification	Inheritance
Wiedemann-Steiner syndrome	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Wiedemann-Steiner syndrome	Definitive	AD

Mondo (10): Wiedemann-Steiner syndrome (MONDO:0011518), neurodevelopmental disorder (MONDO:0700092), intellectual disability (MONDO:0001071), Cornelia de Lange syndrome 1 (MONDO:0007387), autism spectrum disorder (MONDO:0005258), language disorder (MONDO:0004750), Kabuki syndrome 1 (MONDO:0007843), microcephaly (MONDO:0001149), Rubinstein Taybi like syndrome (MONDO:0043195), acute megakaryoblastic leukemia without down syndrome (MONDO:0018004)

Orphanet (7): Wiedemann-Steiner syndrome (Orphanet:319182), Cornelia de Lange syndrome (Orphanet:199), Kabuki syndrome (Orphanet:2322), Rare genetic intellectual disability (Orphanet:183757), Acute megakaryoblastic leukemia in children without Down syndrome (Orphanet:329469), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

104 total (30 of 104 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000268	Dolichocephaly
HP:0000286	Epicanthus
HP:0000311	Round face
HP:0000316	Hypertelorism
HP:0000324	Facial asymmetry
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000369	Low-set ears
HP:0000403	Recurrent otitis media
HP:0000414	Bulbous nose
HP:0000431	Wide nasal bridge
HP:0000437	Depressed nasal tip
HP:0000445	Wide nose
HP:0000455	Broad nasal tip
HP:0000465	Webbed neck
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000506	Telecanthus
HP:0000508	Ptosis
HP:0000527	Long eyelashes
HP:0000574	Thick eyebrow
HP:0000581	Blepharophimosis
HP:0000592	Blue sclerae
HP:0000637	Long palpebral fissure

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST009602_85	Metabolic syndrome	4.000000e-08
GCST010002_199	Refractive error	3.000000e-34
GCST010173_128	Triglyceride levels	1.000000e-10
GCST010241_217	Apolipoprotein A1 levels	1.000000e-09
GCST010242_77	HDL cholesterol levels	2.000000e-08
GCST010244_287	Triglyceride levels	2.000000e-15

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0000195	metabolic syndrome
EFO:0004530	triglyceride measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004612	high density lipoprotein cholesterol measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D007806	Language Disorders	C10.597.606.150.500; C23.888.592.604.150.500
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D065886	Neurodevelopmental Disorders	F03.625
C535877	Rubinstein Taybi like syndrome (supp.)
C536704	Wiedemann Grosse Dibbern syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (5): CHEMBL1293299 (SINGLE PROTEIN), CHEMBL2093861 (PROTEIN-PROTEIN INTERACTION), CHEMBL3137282 (PROTEIN COMPLEX), CHEMBL3883320 (PROTEIN-PROTEIN INTERACTION), CHEMBL4106124 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

535 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 800,028 (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
CHEMBL1057	FLUORESCEIN	4	329,940
CHEMBL1065	METHYSERGIDE	4	8,455
CHEMBL1068	OXCARBAZEPINE	4	16,118
CHEMBL1089641	TRYPAN BLUE FREE ACID	4	113
CHEMBL1116	RALOXIFENE HYDROCHLORIDE	4	28,574
CHEMBL1117	IDARUBICIN	4	136,065
CHEMBL1175	DULOXETINE	4	28,527
CHEMBL1200471	PYRITHIONE ZINC	4	24,834
CHEMBL1200562	HYDROCORTISONE VALERATE	4	10,297
CHEMBL1200750	PROMETHAZINE HYDROCHLORIDE	4	9,776
CHEMBL1200916	THIORIDAZINE HYDROCHLORIDE	4	14,243
CHEMBL1200938	METHYSERGIDE MALEATE	4	4
CHEMBL1201	THIOTHIXENE	4	13,101
CHEMBL1201264	METHANTHELINE	4	3,394
CHEMBL1208422	ROSE BENGAL FREE ACID	4	476
CHEMBL1239	BENZYL BENZOATE	4	162,300
CHEMBL1256842	NOMIFENSINE MALEATE	4	630
CHEMBL1305	ANTAZOLINE	4	9,182
CHEMBL1351	CARBOPLATIN	4
CHEMBL1409	FLUVOXAMINE MALEATE	4	3,999
CHEMBL1417019	MITOXANTRONE HYDROCHLORIDE	4
CHEMBL1511	ESTRADIOL VALERATE	4
CHEMBL1523964	EPHEDRINE SULFATE	4
CHEMBL1554	DACTINOMYCIN	4
CHEMBL1563	DAUNORUBICIN HYDROCHLORIDE	4
CHEMBL1607	TOPOTECAN HYDROCHLORIDE	4
CHEMBL1611	PHENYTOIN SODIUM	4
CHEMBL1657	TAZAROTENE	4
CHEMBL1697	DILTIAZEM HYDROCHLORIDE	4
CHEMBL1709	SERTRALINE HYDROCHLORIDE	4

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
KMT2C Mutation OR KMT2A Mutation	Immunotherapy	Cancer	Sensitivity/Response	CIViC B	EID12031

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — 2.1.1.43 Histone methyltransferases (HMTs)

Binding affinities (BindingDB)

69 measured of 74 human assays (74 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-[5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-3H-pyridine-3-carboxamide	KD	3.5 nM	US-11319299: Substituted carboxamides as inhibitors of WDR5 protein-protein binding
N-[4-chloro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-3H-pyridine-3-carboxamide	KD	10 nM	US-11319299: Substituted carboxamides as inhibitors of WDR5 protein-protein binding
4-[5-[(5-amino-6-chloropyrimidin-4-yl)amino]-2-fluoro-4-(4-methylpiperazin-1-yl)phenyl]-N-(3-morpholin-4-ylpropyl)benzamide	IC50	21 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
US12453731, Example 63	IC50	25 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
N-[4-methyl-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-3H-pyridine-3-carboxamide	KD	26 nM	US-11319299: Substituted carboxamides as inhibitors of WDR5 protein-protein binding
2-amino-N-[4-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-2-fluoro-4-(4-methylpiperazin-1-yl)phenyl]phenyl]acetamide	IC50	33 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
[4-[5-[(5-amino-6-chloropyrimidin-4-yl)amino]-2-fluoro-4-(4-methylpiperazin-1-yl)phenyl]phenyl]-(4-hydroxypiperidin-1-yl)methanone	IC50	33 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
2-amino-N-[4-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-2-fluoro-4-(4-methylpiperazin-1-yl)phenyl]phenyl]-3-methylbutanamide	IC50	34 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
[4-[5-[(5-amino-6-chloropyrimidin-4-yl)amino]-2-fluoro-4-(4-methylpiperazin-1-yl)phenyl]phenyl]-morpholin-4-ylmethanone	IC50	36 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
4-[5-[(5-amino-6-chloropyrimidin-4-yl)amino]-2-fluoro-4-(4-methylpiperazin-1-yl)phenyl]-N-(oxan-4-ylmethyl)benzamide	IC50	36 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
methyl 4-[5-[(5-amino-6-chloropyrimidin-4-yl)amino]-2-fluoro-4-(4-methylpiperazin-1-yl)phenyl]benzoate	IC50	40 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
4-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-2-fluoro-4-(4-methylpiperazin-1-yl)phenyl]-N-(3-morpholin-4-ylpropyl)benzamide	IC50	69 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
4-[5-[(5-amino-6-chloropyrimidin-4-yl)amino]-2-fluoro-4-(4-methylpiperazin-1-yl)phenyl]-N-(2-morpholin-4-ylethyl)benzamide	IC50	74 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
N-[4-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-2-fluoro-4-(4-methylpiperazin-1-yl)phenyl]phenyl]-2-(oxan-4-yl)acetamide	IC50	85 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
(R)-N-ethyl-5-fluoro-2-((5-(2-(6-((2-hydroxyethyl)(methyl)amino)-2-methylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)-N-isopropylbenzamide	IC50	96 nM	US-12473295: Substituted straight chain spiro derivatives
4-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-2-fluoro-4-(4-methylpiperazin-1-yl)phenyl]-N-(2-morpholin-4-ylethyl)benzamide	IC50	102 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
N-[4-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-2-fluoro-4-(4-methylpiperazin-1-yl)phenyl]phenyl]-1-methylpiperidine-4-carboxamide	IC50	105 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
[4-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-2-fluoro-4-(4-methylpiperazin-1-yl)phenyl]phenyl]-(4-ethylpiperazin-1-yl)methanone	IC50	112 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
[4-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-2-fluoro-4-(4-methylpiperazin-1-yl)phenyl]phenyl]-morpholin-4-ylmethanone	IC50	117 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
[1-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-4-(4-methylpiperazin-1-yl)phenyl]triazol-4-yl]-(4-methylpiperazin-1-yl)methanone	IC50	164 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
4-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-4-(4-methylpiperazin-1-yl)phenyl]-N-(3-morpholin-4-ylpropyl)benzamide	IC50	165 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
N-[4-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-2-fluoro-4-(4-methylpiperazin-1-yl)phenyl]phenyl]oxane-4-carboxamide	IC50	176 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
4-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-4-(4-methylpiperazin-1-yl)phenyl]-N-(2-morpholin-4-ylethyl)benzamide	IC50	183 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
[4-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-4-(4-methylpiperazin-1-yl)phenyl]phenyl]-morpholin-4-ylmethanone	IC50	186 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
[4-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-4-(4-methylpiperazin-1-yl)phenyl]phenyl]-(4-methylpiperazin-1-yl)methanone	IC50	217 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
[1-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-4-(4-methylpiperazin-1-yl)phenyl]triazol-4-yl]-morpholin-4-ylmethanone	IC50	240 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
4-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-2-fluoro-4-(4-methylpiperazin-1-yl)phenyl]-N,N-dimethylbenzamide	IC50	240 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
N-[4-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-4-(4-methylpiperazin-1-yl)phenyl]phenyl]butanamide	IC50	261 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
US12453731, Example 28	IC50	270 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
N-[4-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-4-(4-methylpiperazin-1-yl)phenyl]phenyl]-1-methylpiperidine-4-carboxamide	IC50	287 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
4-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-4-(4-methylpiperazin-1-yl)phenyl]-N-(3-hydroxypropyl)benzamide	IC50	310 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
methyl 4-[5-[(5-amino-6-chloropyrimidin-4-yl)amino]-2-methyl-4-(4-methylpiperazin-1-yl)phenyl]benzoate	IC50	316 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
N-[3-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-4-(4-methylpiperazin-1-yl)phenyl]phenyl]oxane-4-carboxamide	IC50	328 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
N-[3-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-4-(4-methylpiperazin-1-yl)phenyl]phenyl]-1-methylpiperidine-4-carboxamide	IC50	329 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
4-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-4-(4-methylpiperazin-1-yl)phenyl]-N,N-dimethylbenzamide	IC50	360 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
4-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-4-(4-methylpiperazin-1-yl)phenyl]-N-(2-pyrrolidin-1-ylethyl)benzamide	IC50	370 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
N-[4-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-4-(4-methylpiperazin-1-yl)phenyl]phenyl]cyclohexanecarboxamide	IC50	372 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
N-ethyl-2-[[5-[2-[(3R)-6-[ethyl(2-methoxyethyl)amino]-2-methylhexan-3-yl]-2,7-diazaspiro[3.4]octan-7-yl]-1,2,4-triazin-6-yl]oxy]-5-fluoro-N-propan-2-ylbenzamide	IC50	380 nM	US-12473295: Substituted straight chain spiro derivatives
4-[3-[4-(cyclopentyl-hydroxy-phenylmethyl)piperidin-1-yl]propoxy]benzonitrile	IC50	390 nM	US-20260007675: TARGETING CHROMATIN REGULATORS INHIBITS LEUKEMOGENIC GENE EXPRESSION IN NPM1 MUTANT LEUKEMIA
4-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-4-(4-methylpiperazin-1-yl)phenyl]-N-propan-2-ylbenzamide	IC50	460 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
4-[5-[(5-amino-6-chloropyrimidin-4-yl)amino]-2-methyl-4-(4-methylpiperazin-1-yl)phenyl]-N-(3-morpholin-4-ylpropyl)benzamide	IC50	465 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
N-[4-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-4-(4-methylpiperazin-1-yl)phenyl]phenyl]oxane-4-carboxamide	IC50	489 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
6-chloro-4-N-[2-(4-methylpiperazin-1-yl)-5-pyridin-4-ylphenyl]pyrimidine-4,5-diamine	IC50	560 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
[4-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-4-(4-methylpiperazin-1-yl)phenyl]-3-fluorophenyl]-(4-methylpiperazin-1-yl)methanone	IC50	652 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
4-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-2-methyl-4-(4-methylpiperazin-1-yl)phenyl]-N,N-dimethylbenzamide	IC50	671 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
4-N-[5-(3-aminophenyl)-2-(4-methylpiperazin-1-yl)phenyl]-6-chloropyrimidine-4,5-diamine	IC50	675 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
4-N-[5-(4-aminophenyl)-2-(4-methylpiperazin-1-yl)phenyl]-6-chloropyrimidine-4,5-diamine	IC50	691 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
1-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-4-(4-methylpiperazin-1-yl)phenyl]-N,N-dimethyltriazole-4-carboxamide	IC50	860 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
methyl 1-[3-[(5-amino-6-chloropyrimidin-4-yl)amino]-4-(4-methylpiperazin-1-yl)phenyl]triazole-4-carboxylate	IC50	865 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof
US12453731, Example 48	IC50	1090 nM	US-12453731: Aniline-based WDR5 protein-protein interaction inhibitor, and preparation method and use thereof

ChEMBL bioactivities

6100 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.30	IC50	0.5	nM	CHEMBL5272148
9.30	IC50	0.5	nM	CHEMBL5414266
9.29	IC50	0.51	nM	CHEMBL5272148
9.08	IC50	0.83	nM	CHEMBL4216333
9.05	IC50	0.9	nM	CHEMBL3798088
9.00	IC50	1	nM	CHEMBL5282452
9.00	Potency	1	nM	CHEMBL1409198
8.89	Potency	1.3	nM	CHEMBL1532950
8.66	IC50	2.2	nM	CHEMBL5723335
8.63	IC50	2.35	nM	CHEMBL4788214
8.62	IC50	2.4	nM	CHEMBL3883592
8.54	IC50	2.9	nM	CHEMBL3799591
8.52	IC50	3	nM	CHEMBL4435830
8.48	IC50	3.3	nM	CHEMBL4435830
8.39	IC50	4.1	nM	CHEMBL6017372
8.35	IC50	4.5	nM	CHEMBL3957384
8.34	IC50	4.6	nM	CHEMBL4777030
8.33	IC50	4.7	nM	CHEMBL5277316
8.33	Ki	4.7	nM	CHEMBL6144085
8.28	IC50	5.3	nM	CHEMBL6067935
8.21	IC50	6.2	nM	CHEMBL6019747
8.21	IC50	6.2	nM	CHEMBL5808345
8.17	IC50	6.8	nM	CHEMBL4588661
8.15	IC50	7	nM	CHEMBL5192780
8.15	IC50	7	nM	CHEMBL5426151
8.15	IC50	7.1	nM	CHEMBL6067936
8.15	IC50	7	nM	CHEMBL5956903
8.10	IC50	8	nM	CHEMBL4209303
8.10	IC50	8	nM	CHEMBL5272633
8.10	IC50	8	nM	CHEMBL5303542
8.10	IC50	7.9	nM	CHEMBL5803279
8.08	IC50	8.4	nM	CHEMBL5957518
8.07	IC50	8.6	nM	CHEMBL5562523
8.05	Potency	8.9	nM	CHEMBL1256364
8.05	Potency	8.9	nM	CHEMBL1525427
8.05	Potency	8.9	nM	CHEMBL1329073
8.01	IC50	9.8	nM	CHEMBL5573350
8.00	IC50	10	nM	CHEMBL5182826
7.96	IC50	11	nM	CHEMBL5784558
7.95	IC50	11.3	nM	CHEMBL5579746
7.95	IC50	11.27	nM	CHEMBL6146418
7.95	Potency	11.2	nM	CHEMBL545050
7.94	IC50	11.4	nM	CHEMBL5886049
7.92	IC50	12	nM	CHEMBL3781211
7.91	IC50	12.29	nM	CHEMBL6147464
7.90	IC50	12.6	nM	CHEMBL4073865
7.90	IC50	12.7	nM	CHEMBL4103117
7.90	Potency	12.6	nM	CHEMBL1329367
7.89	IC50	12.92	nM	CHEMBL6149969
7.88	IC50	13.3	nM	CHEMBL6196036

PubChem BioAssay actives

283 with measured affinity, of 566 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
N-[3-[[2-cyano-4-methyl-5-[[4-[[2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]indol-1-yl]methyl]-1-bicyclo[1.1.1]pentanyl]formamide	1925952: Inhibition of human Menin to MLL protein-protein interaction	ic50	0.0005	uM
N-[3-[[2-cyano-4-methyl-5-[[4-[[2-(methylamino)-6-(3,3,3-trifluoropropyl)thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]indol-1-yl]methyl]-1-bicyclo[1.1.1]pentanyl]formamide	1980330: Inhibition of human menin/MLL protein-protein interaction by competition based fluorescence polarization assay	ic50	0.0005	uM
4-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-cyclopentyl-2-phenylbutan-1-amine	1925952: Inhibition of human Menin to MLL protein-protein interaction	ic50	0.0008	uM
N-[(3R,6S,9S,12R)-9-[3-(diaminomethylideneamino)propyl]-6-ethyl-12-methyl-2,5,8,11-tetraoxo-3-phenyl-1,4,7,10-tetrazacyclohexadec-12-yl]-2-methylpropanamide	1372681: Inhibition of MLL1-WDR5 (unknown origin) protein-protein interaction by fluorescence-labeled Ac-ARA peptide tracer based fluorescence polarization assay	ic50	0.0009	uM
(1R,9S)-11-(2-hydroxy-5-phenylpentyl)-1,9-dimethyl-7,11-diazatricyclo[7.3.1.02,7]trideca-2,4-dien-6-one	1925950: Inhibition of Menin to MLL (unknown origin) protein-protein interaction	ic50	0.0010	uM
N-benzhydryl-1-[[(2S)-5-(diaminomethylideneamino)-2-[[2-ethyl-2-(2-methylpropanoylamino)butanoyl]amino]pentanoyl]amino]cyclopentane-1-carboxamide	1372680: Inhibition of MLL1 binding to N-terminal His-tagged WRD5 23 deletion mutant (24 to 334 residues) (unknown origin) expressed in Escherichia coli Rosetta 2 (DE3) pLysS cells by fluorescence polarization assay	ki	0.0010	uM
N-[bis(4-chlorophenyl)methyl]-1-[[(2S)-5-(diaminomethylideneamino)-2-[[2-ethyl-2-(2-methylpropanoylamino)butanoyl]amino]pentanoyl]amino]cyclopentane-1-carboxamide	1372680: Inhibition of MLL1 binding to N-terminal His-tagged WRD5 23 deletion mutant (24 to 334 residues) (unknown origin) expressed in Escherichia coli Rosetta 2 (DE3) pLysS cells by fluorescence polarization assay	ki	0.0010	uM
N-[bis(4-fluorophenyl)methyl]-1-[[(2S)-5-(diaminomethylideneamino)-2-[[2-ethyl-2-(2-methylpropanoylamino)butanoyl]amino]pentanoyl]amino]cyclopentane-1-carboxamide	1372680: Inhibition of MLL1 binding to N-terminal His-tagged WRD5 23 deletion mutant (24 to 334 residues) (unknown origin) expressed in Escherichia coli Rosetta 2 (DE3) pLysS cells by fluorescence polarization assay	ki	0.0010	uM
(2S)-1-[(3S,6S,8Z,11S,17S)-6-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamidopropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-[(3-fluorophenyl)methyl]-2,5,13,16-tetraoxospiro[1,4,12,15-tetrazabicyclo[15.3.0]icos-8-ene-14,1’-cyclobutane]-11-carbonyl]-N-[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]pyrrolidine-2-carboxamide	1743094: Inhibition of Menin-MLL protein-protein interaction (unknown origin) preincubated for 1 hr in presence of FLSN-MLL4-43 peptide followed by compound addition and measured after 1 hr by fluorescence polarization assay	ic50	0.0024	uM
methyl N-[(1S,2R)-2-[(S)-cyano-[1-[[1-[4-[1-[(E)-4-(dimethylamino)but-2-enoyl]azetidin-3-yl]sulfonylphenyl]azetidin-3-yl]methyl]piperidin-4-yl]-(3-fluorophenyl)methyl]cyclopentyl]carbamate	1980333: Inhibition of menin (unknown origin)/MLL (unknown origin) protein-protein interaction by fluorescence polarization assay	ic50	0.0030	uM
(2S)-1-[(3S,6S,11S,17S)-6-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamidopropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-[(3-fluorophenyl)methyl]-2,5,13,16-tetraoxospiro[1,4,12,15-tetrazabicyclo[15.3.0]icosane-14,1’-cyclobutane]-11-carbonyl]-N-[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]pyrrolidine-2-carboxamide	1743094: Inhibition of Menin-MLL protein-protein interaction (unknown origin) preincubated for 1 hr in presence of FLSN-MLL4-43 peptide followed by compound addition and measured after 1 hr by fluorescence polarization assay	ic50	0.0046	uM
7-chloro-N-[2-[4-[7-[4-[2-[(7-chloroquinolin-4-yl)amino]ethyl]piperazin-1-yl]heptyl]piperazin-1-yl]ethyl]quinolin-4-amine	1925952: Inhibition of human Menin to MLL protein-protein interaction	ic50	0.0047	uM
2-[(3,5-dimethoxyphenyl)methyl]-5-(4-fluoro-2-methylphenyl)-7-[(2-imino-3-methylimidazol-1-yl)methyl]-3,4-dihydroisoquinolin-1-one	2097542: Inhibition of MLL1/WDR5 (unknown origin) protein-protein interaction incubated for 60 mins by HTRF analysis	ic50	0.0068	uM
methyl N-[(1S,2R)-2-[(S)-cyano-[1-[[1-(4-cyclobutylsulfonylphenyl)azetidin-3-yl]methyl]piperidin-4-yl]-(3-fluorophenyl)methyl]cyclopentyl]carbamate	1980333: Inhibition of menin (unknown origin)/MLL (unknown origin) protein-protein interaction by fluorescence polarization assay	ic50	0.0070	uM
N-[1-[[1-(4-cyclopropylsulfonylphenyl)azetidin-3-yl]methyl]piperidin-4-yl]-6-[2-(dimethylamino)ethoxy]pyrido[3,2-d]pyrimidin-4-amine	1852518: Inhibition of Menin/fluorescein labeled MLL(4 to 43 residues) (unknown origin) protein protein interaction incubated for 1 hr by fluorescence polarization-based competitive binding assay	ic50	0.0070	uM
4-[2-[(1R)-1-(azetidin-3-yl)-2-methylpropyl]-2,7-diazaspiro[3.4]octan-7-yl]-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine	1387534: Inhibition of menin-MLL1 (unknown origin) protein-protein interaction by HTRF assay	ic50	0.0080	uM
2-[2-cyano-4-methyl-5-[[2-[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[3.5]nonan-7-yl]methyl]indol-1-yl]acetamide	2068386: Inhibition of human menin-MLL (unknown origin) protein-protein interaction incubated for 0.5 to 4 hrs by TR-FRET assay	ic50	0.0080	uM
2-[2-cyano-4-methyl-5-[[2-[6-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2,7-diazaspiro[3.5]nonan-7-yl]methyl]indol-1-yl]acetamide	1925952: Inhibition of human Menin to MLL protein-protein interaction	ic50	0.0080	uM
N-[(2R)-3-(4-chlorophenyl)-1-(methylamino)-1-oxopropan-2-yl]-3-[5-(hydroxymethyl)-2-methylphenyl]-5-[(5-methyl-1H-imidazol-4-yl)methylamino]benzamide	2097542: Inhibition of MLL1/WDR5 (unknown origin) protein-protein interaction incubated for 60 mins by HTRF analysis	ic50	0.0086	uM
N-[(2R)-3-(4-chlorophenyl)-1-(methylamino)-1-oxopropan-2-yl]-3-[4-chloro-2-(trifluoromethyl)phenyl]-5-[(5-methyl-1H-imidazol-4-yl)methylamino]benzamide	2097542: Inhibition of MLL1/WDR5 (unknown origin) protein-protein interaction incubated for 60 mins by HTRF analysis	ic50	0.0098	uM
6-[2-(dimethylamino)ethoxy]-N-[1-[[1-(4-pyridin-4-ylsulfonylphenyl)azetidin-3-yl]methyl]piperidin-4-yl]pyrido[3,2-d]pyrimidin-4-amine	1852518: Inhibition of Menin/fluorescein labeled MLL(4 to 43 residues) (unknown origin) protein protein interaction incubated for 1 hr by fluorescence polarization-based competitive binding assay	ic50	0.0100	uM
N-[(2R)-3-(4-chlorophenyl)-1-(methylamino)-1-oxopropan-2-yl]-3-[(5-methyl-1H-imidazol-4-yl)methylamino]-5-(2-methylsulfanylphenyl)benzamide	2097542: Inhibition of MLL1/WDR5 (unknown origin) protein-protein interaction incubated for 60 mins by HTRF analysis	ic50	0.0113	uM
6-methoxy-4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]indole-2-carbonitrile	1286398: Inhibition of menin-MLL interaction (unknown origin) after 1 hr by fluorescence polarization assay	ic50	0.0120	uM
N-[(3R,6S,9S,12R)-9-[3-(diaminomethylideneamino)propyl]-6-ethyl-12-methyl-2,5,8,11-tetraoxo-3-phenyl-1,4,7,10-tetrazacyclotetradec-12-yl]-2-methylpropanamide;2,2,2-trifluoroacetic acid	1449556: Inhibition of human N-terminal GST-tagged MLL1 (3735 to 3973 residues) interaction with human full length N-terminal 6xHis-tagged ASH2L/N-terminal 6xHis-tagged human full length RbBP5/human N-terminal 6xHis-tagged WDR5/human full length N-terminal 6xHis-tagged DPY30 assessed as decrease in H3K4me1-2 methylation preincubated for 30 mins followed by SAM/nucleosome mixture addition measured after 120 mins in absence of light by AlphaLISA assay	ic50	0.0126	uM
N-[(3R,6S,9S,12R)-6-ethyl-12-methyl-9-[3-[(N’-methylcarbamimidoyl)amino]propyl]-2,5,8,11-tetraoxo-3-phenyl-1,4,7,10-tetrazacyclotetradec-12-yl]-2-methylpropanamide;2,2,2-trifluoroacetic acid	1449556: Inhibition of human N-terminal GST-tagged MLL1 (3735 to 3973 residues) interaction with human full length N-terminal 6xHis-tagged ASH2L/N-terminal 6xHis-tagged human full length RbBP5/human N-terminal 6xHis-tagged WDR5/human full length N-terminal 6xHis-tagged DPY30 assessed as decrease in H3K4me1-2 methylation preincubated for 30 mins followed by SAM/nucleosome mixture addition measured after 120 mins in absence of light by AlphaLISA assay	ic50	0.0127	uM
(2S)-1-[(3S,6S,11S,17S)-6-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamidopropanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-[(3-fluorophenyl)methyl]-2,5,13,16-tetraoxospiro[1,4,12,15-tetrazabicyclo[15.3.0]icosane-14,1’-cyclobutane]-11-carbonyl]-N-[(2S)-5-amino-1-[[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]pyrrolidine-2-carboxamide	1743094: Inhibition of Menin-MLL protein-protein interaction (unknown origin) preincubated for 1 hr in presence of FLSN-MLL4-43 peptide followed by compound addition and measured after 1 hr by fluorescence polarization assay	ic50	0.0140	uM
4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]indole-2-carbonitrile	1286398: Inhibition of menin-MLL interaction (unknown origin) after 1 hr by fluorescence polarization assay	ic50	0.0140	uM
4-methyl-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]-1H-indole-2-carbonitrile	1286398: Inhibition of menin-MLL interaction (unknown origin) after 1 hr by fluorescence polarization assay	ic50	0.0150	uM
(2S)-2-amino-4-[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl-[[1-(thiophen-3-ylmethyl)azetidin-3-yl]methyl]amino]butanoic acid	1658842: Inhibition of recombinant human MLL1 complex (MLL1/Ash2L/RbBP5/WDR5/DPY-30) expressed in Escherichia coli Rosetta 2 (DE3) cells using H3 (1 to 21) peptide as substrate incubated for 1 hr in presence of 3[H] SAM by AlphaLISA assay	ic50	0.0152	uM
2-[(4-chlorophenyl)methyl]-5-[5-(hydroxymethyl)-2-methylphenyl]-7-[(5-methyl-1H-imidazol-4-yl)methylamino]-3,4-dihydroisoquinolin-1-one	2097542: Inhibition of MLL1/WDR5 (unknown origin) protein-protein interaction incubated for 60 mins by HTRF analysis	ic50	0.0155	uM
1-(2-hydroxyethyl)-6-methoxy-4-methyl-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]indole-2-carbonitrile	1286398: Inhibition of menin-MLL interaction (unknown origin) after 1 hr by fluorescence polarization assay	ic50	0.0160	uM
6-methoxy-4-methyl-1-(2H-triazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]indole-2-carbonitrile	1286398: Inhibition of menin-MLL interaction (unknown origin) after 1 hr by fluorescence polarization assay	ic50	0.0160	uM
6-hydroxy-4-methyl-1-(2H-triazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]indole-2-carbonitrile	1286398: Inhibition of menin-MLL interaction (unknown origin) after 1 hr by fluorescence polarization assay	ic50	0.0170	uM
2-[2-(4-chlorophenyl)ethyl]-5-[5-(hydroxymethyl)-2-methylphenyl]-7-[(5-methyl-1H-imidazol-4-yl)methylamino]-3,4-dihydroisoquinolin-1-one	2097542: Inhibition of MLL1/WDR5 (unknown origin) protein-protein interaction incubated for 60 mins by HTRF analysis	ic50	0.0172	uM
6-hydroxy-4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]indole-2-carbonitrile	1286398: Inhibition of menin-MLL interaction (unknown origin) after 1 hr by fluorescence polarization assay	ic50	0.0180	uM
N-[(2R)-3-(4-chlorophenyl)-1-(methylamino)-1-oxopropan-2-yl]-3-(2-cyclopropylphenyl)-5-[(5-methyl-1H-imidazol-4-yl)methylamino]benzamide	2097542: Inhibition of MLL1/WDR5 (unknown origin) protein-protein interaction incubated for 60 mins by HTRF analysis	ic50	0.0188	uM
N-[(3,5-dichlorophenyl)methyl]-3-[(3-methyl-2-oxoimidazol-1-yl)methyl]-5-(2-methyl-3-pyridinyl)benzamide	1895591: Inhibition of MLL1 (unknown origin) histone methyltransferase activity	ic50	0.0200	uM
6-hydroxy-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]-1H-indole-2-carbonitrile	1286398: Inhibition of menin-MLL interaction (unknown origin) after 1 hr by fluorescence polarization assay	ic50	0.0200	uM
6-hydroxy-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]indole-2-carbonitrile	1286398: Inhibition of menin-MLL interaction (unknown origin) after 1 hr by fluorescence polarization assay	ic50	0.0210	uM
(2S)-2-amino-4-[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl-[[1-(furan-3-ylmethyl)azetidin-3-yl]methyl]amino]butanoic acid	1658842: Inhibition of recombinant human MLL1 complex (MLL1/Ash2L/RbBP5/WDR5/DPY-30) expressed in Escherichia coli Rosetta 2 (DE3) cells using H3 (1 to 21) peptide as substrate incubated for 1 hr in presence of 3[H] SAM by AlphaLISA assay	ic50	0.0218	uM
4-[4-(5,5-dimethyl-4H-1,3-thiazol-2-yl)piperazin-1-yl]-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine	1231905: Inhibition of menin-MLL1 interaction (unknown origin)	kd	0.0220	uM
6-methoxy-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]-1H-indole-2-carbonitrile	1286398: Inhibition of menin-MLL interaction (unknown origin) after 1 hr by fluorescence polarization assay	ic50	0.0220	uM
4-chloro-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]-1H-indole-2-carbonitrile	1286398: Inhibition of menin-MLL interaction (unknown origin) after 1 hr by fluorescence polarization assay	ic50	0.0220	uM
4-methyl-1-(2H-triazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]indole-2-carbonitrile	1286398: Inhibition of menin-MLL interaction (unknown origin) after 1 hr by fluorescence polarization assay	ic50	0.0230	uM
1-(3-hydroxy-2-propan-2-yloxypropyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]indole-2-carbonitrile	1286398: Inhibition of menin-MLL interaction (unknown origin) after 1 hr by fluorescence polarization assay	ic50	0.0230	uM
1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]indole-2-carbonitrile	1286398: Inhibition of menin-MLL interaction (unknown origin) after 1 hr by fluorescence polarization assay	ic50	0.0230	uM
(2S)-2-acetamido-N-[(2S)-1-[[(3S,6S,9S,15R,28S)-15-benzyl-3-[3-(diaminomethylideneamino)propyl]-6-methyl-2,5,8,14,17,27-hexaoxo-1,4,7,13,16,26-hexazatricyclo[26.3.0.09,13]hentriacontan-18-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]-5-(diaminomethylideneamino)pentanamide	1272636: Inhibition of menin-MLL (unknown origin) interaction	ki	0.0238	uM
6-methoxy-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]indole-2-carbonitrile	1286398: Inhibition of menin-MLL interaction (unknown origin) after 1 hr by fluorescence polarization assay	ic50	0.0240	uM
2-[2-cyano-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]indol-1-yl]acetamide	1286398: Inhibition of menin-MLL interaction (unknown origin) after 1 hr by fluorescence polarization assay	ic50	0.0250	uM
3-bromo-N-[(2R)-3-(4-chlorophenyl)-1-(methylamino)-1-oxopropan-2-yl]-5-[(5-methyl-1H-imidazol-4-yl)methylamino]benzamide	2097542: Inhibition of MLL1/WDR5 (unknown origin) protein-protein interaction incubated for 60 mins by HTRF analysis	ic50	0.0252	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression	6
trichostatin A	affects cotreatment, decreases expression	3
Etoposide	increases cleavage, increases mutagenesis, increases response to substance	3
methylmercuric chloride	increases expression	2
Cadmium	decreases expression, increases abundance	2
Cisplatin	decreases expression, affects response to substance	2
Doxorubicin	decreases response to substance	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Quercetin	decreases expression, increases mutagenesis	2
Tretinoin	decreases expression	2
Cadmium Chloride	decreases expression, increases abundance	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
Permethrin	increases mutagenesis	2
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
geldanamycin	increases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
kaempferol	increases mutagenesis	1
bisphenol A	decreases expression, increases methylation	1
deoxynivalenol	decreases reaction, increases expression, affects binding, increases reaction	1
2-butenal	decreases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	increases expression	1
butyraldehyde	decreases expression	1
nickel chloride	increases expression	1
nonylphenol	increases expression	1
benzo(e)pyrene	increases methylation	1

ChEMBL screening assays

188 unique, capped per target: 180 binding, 8 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1614410	Functional	PUBCHEM_BIOASSAY: qHTS Fluorescence Polarization Assay for Inhibitors of MLL CXXC domain - DNA interaction. (Class of assay: confirmatory) [Related pubchem assays: 2698 (Summary assay.)]	PubChem BioAssay data set
CHEMBL2209114	Binding	Inhibition of MLL1 using core histone as substrate preincubated for 10 mins followed by addition of [3H]SAM and incubated for 60 mins	Identification of Potent, Selective, Cell-Active Inhibitors of the Histone Lysine Methyltransferase EZH2. — ACS Med Chem Lett

Cellosaurus cell lines

556 cell lines: 548 cancer cell line, 4 transformed cell line, 3 embryonic stem cell, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_0006	THP-1	Cancer cell line	Male
CVCL_0064	MV4-11	Cancer cell line	Male
CVCL_0081	BEL-1	Cancer cell line	Female
CVCL_0093	RS4;11	Cancer cell line	Female
CVCL_0095	SEM	Cancer cell line	Female
CVCL_0R21	THP-1/DC-SIGN	Cancer cell line	Male
CVCL_0R25	THP-1(NCI)	Cancer cell line	Male
CVCL_0R26	THP-1(NCI)/DC-SIGN	Cancer cell line	Male
CVCL_1069	ALL-PO	Cancer cell line	Female
CVCL_1326	Karpas-45	Cancer cell line	Male

Clinical trials (associated diseases)

298 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,
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
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
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
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
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
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
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
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