MGMT

Summary

MGMT (O-6-methylguanine-DNA methyltransferase, HGNC:7059) is a protein-coding gene on chromosome 10q26.3, encoding Methylated-DNA–protein-cysteine methyltransferase (P16455). Involved in the cellular defense against the biological effects of O6-methylguanine (O6-MeG) and O4-methylthymine (O4-MeT) in DNA. In precision oncology, MGMT Promoter Methylation confers sensitivity to Temozolomide in Glioblastoma (CIViC Level A); 8 further curated variant–drug associations are listed below.

Alkylating agents are potent carcinogens that can result in cell death, mutation and cancer. The protein encoded by this gene is a DNA repair protein that is involved in cellular defense against mutagenesis and toxicity from alkylating agents. The protein catalyzes transfer of methyl groups from O(6)-alkylguanine and other methylated moieties of the DNA to its own molecule, which repairs the toxic lesions. Methylation of the genes promoter has been associated with several cancer types, including colorectal cancer, lung cancer, lymphoma and glioblastoma.

Source: NCBI Gene 4255 — RefSeq curated summary.

At a glance

• GWAS associations: 23
• Clinical variants (ClinVar): 57 total — 1 likely-pathogenic
• Phenotypes (HPO): 11
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 9 curated variant–drug associations
• MANE Select transcript: NM_002412

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7059
Approved symbol	MGMT
Name	O-6-methylguanine-DNA methyltransferase
Location	10q26.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000170430
Ensembl biotype	protein_coding
OMIM	156569
Entrez	4255

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 21 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000306010, ENST00000462672, ENST00000482547, ENST00000482653, ENST00000651593, ENST00000897068, ENST00000897069, ENST00000897070, ENST00000897071, ENST00000897072, ENST00000897073, ENST00000897074, ENST00000897075, ENST00000897076, ENST00000897077, ENST00000897078, ENST00000897079, ENST00000897080, ENST00000897081, ENST00000932196, ENST00000932197, ENST00000932198, ENST00000963416, ENST00000963417

RefSeq mRNA: 1 — MANE Select: NM_002412 NM_002412

CCDS: CCDS7660

Canonical transcript exons

ENST00000651593 — 5 exons

Exon	Start	End
ENSE00001144049	129759202	129759341
ENSE00003612185	129707895	129708043
ENSE00003842257	129467241	129467296
ENSE00003846587	129766788	129770983
ENSE00003847553	129536241	129536377

Expression profiles

Bgee: expression breadth ubiquitous, 261 present calls, max score 96.29.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.3608 / max 150.2202, expressed in 1577 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
107677	7.8857	1514
107676	7.4750	1540

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	96.29	gold quality
liver	UBERON:0002107	93.61	gold quality
endometrium epithelium	UBERON:0004811	90.10	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.80	gold quality
right uterine tube	UBERON:0001302	89.56	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	89.39	gold quality
omental fat pad	UBERON:0010414	89.15	gold quality
peritoneum	UBERON:0002358	89.14	gold quality
adipose tissue of abdominal region	UBERON:0007808	88.82	gold quality
body of stomach	UBERON:0001161	88.46	gold quality
tendon of biceps brachii	UBERON:0008188	88.40	gold quality
body of pancreas	UBERON:0001150	88.36	gold quality
apex of heart	UBERON:0002098	88.18	gold quality
mucosa of stomach	UBERON:0001199	87.87	gold quality
gall bladder	UBERON:0002110	87.81	gold quality
right atrium auricular region	UBERON:0006631	87.76	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.41	gold quality
triceps brachii	UBERON:0001509	87.32	gold quality
left coronary artery	UBERON:0001626	87.31	gold quality
right adrenal gland cortex	UBERON:0035827	87.23	gold quality
left ovary	UBERON:0002119	87.05	gold quality
skin of abdomen	UBERON:0001416	87.03	gold quality
subcutaneous adipose tissue	UBERON:0002190	86.97	gold quality
left adrenal gland cortex	UBERON:0035825	86.79	gold quality
ascending aorta	UBERON:0001496	86.70	gold quality
right adrenal gland	UBERON:0001233	86.68	gold quality
lower esophagus mucosa	UBERON:0035834	86.68	gold quality
adipose tissue	UBERON:0001013	86.64	gold quality
tibial artery	UBERON:0007610	86.64	gold quality
thoracic aorta	UBERON:0001515	86.61	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.15
E-MTAB-7606	no	1188.25

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, APEX1, ASCL1, CHAF1A, CHAF1B, CTNNBL1, DNMT1, DNMT3A, EP300, FOS, FOXC1, GATA3, GATA4, GATA5, GLI1, HDAC1, IFNB1, JUN, MBD1, MECP2, MYC, NFKB, PAX1, RELA, SP1, TFCP2, TP53, TP63, TP73, ZNF699

miRNA regulators (miRDB)

31 targeting MGMT, 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-1252-5P	100.00	69.80	2774
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-8076	99.78	68.52	1170
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-5583-3P	99.06	65.68	1018
HSA-MIR-6770-5P	98.97	66.76	1853
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-1537-5P	98.70	68.33	999
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-4436B-3P	98.25	65.26	1494
HSA-MIR-6735-5P	98.24	65.36	1488
HSA-MIR-7843-5P	98.12	65.26	1421
HSA-MIR-4736	97.96	65.89	1287
HSA-MIR-4632-5P	97.82	65.38	1470
HSA-MIR-6893-3P	97.79	64.91	1238
HSA-MIR-6879-5P	97.77	65.52	1521
HSA-MIR-663B	97.40	62.91	664
HSA-MIR-370-3P	97.09	64.92	1221
HSA-MIR-3622A-3P	97.06	66.43	1000
HSA-MIR-4793-5P	96.88	65.90	872
HSA-MIR-3622B-3P	96.82	66.36	988
HSA-MIR-6735-3P	96.10	63.81	600
HSA-MIR-5002-3P	95.75	67.04	542
HSA-MIR-885-3P	95.14	63.08	448

Literature-anchored findings (GeneRIF, showing 40)

• The modified human DNA repair enzyme O(6)-methylguanine-DNA methyltransferase is a negative regulator of estrogen receptor-mediated transcription upon alkylation DNA damage. (PMID:11564893)
• O(6)-Methylguanine-DNA methyltransferase promoter hypermethylation shifts the p53 mutational spectrum in non-small cell lung cancer. (PMID:11719438)
• MGMT is an important resistant determinant to camptothecin derivatives and may play role in TOPO 1-mediated DNA damage and/or the repair processes (PMID:11802813)
• No promoter hypermethylation of MGMT was found in either metaplastic or non-metaplastic intestinal mucosae. (PMID:11872960)
• O6-Alkylguanine-DNA-alkyltransferase activity in peripheral leukocytes (PMID:11911967)
• Glutathione S-transferase P1 and NADPH quinone oxidoreductase polymorphisms are associated with aberrant promoter methylation of P16(INK4a) and O(6)-methylguanine-DNA methyltransferase in sputum. (PMID:11956078)
• Impaired production of MGMT and hypermethylation of the MGMT promoter in retinoblastoma tissues. (PMID:11980845)
• heterogeneously expressed in breast tumors (PMID:12087469)
• substrate specificity and sequence preferenceof G:T mismatch repair (PMID:12119040)
• Among the dacarbazine responders a larger proportion (50%) had melanomas containing less than 50% MGMT-positive tumour cells than among the non-responders (23%). This is consistent with the hypothesis that MGMT contributes to DTIC resistance. (PMID:12170182)
• purified E6 protein promoted the degradation of rMGMT in rabbit reticulocyte lysates. Immunoprecipitation assays showed the presence of a ternary protein complex between MGMT, E6, and the cellular ubiquitin-ligase E6-associated protein (E6-AP) (PMID:12185595)
• Mutation analysis of K-ras and beta-catenin genes related to this and mismatch repair protein status in human gallbladder carcinoma. (PMID:12469220)
• inactivation of MGMT contributes to development of nonseminomatous testicular cancer (PMID:12483540)
• a significantly increased frequency of G:C to A:T mutations of the p53 gene in brain tumors having a methylated MGMT promoter compared with those having an unmethylated MGMT promoter (PMID:12503076)
• The presence of zinc on MGMT has a functional effect indicated by the enhanced rate of alkyl transfer from either O6-methylguanine in DNA or O6-benzylguanine; zinc binding also improves conformational stability and enhances correct folding of the protein. (PMID:12549918)
• CpG methylation of MGMT and hMLH1 promoter in hepatocellular carcinoma associated with hepatitis viral infection. (PMID:12592365)
• loss of expression of MGMT occurs more frequently in cancer than in adenoma in both sporadic and familial adenomatous polyposis patients, and loss of expression of MGMT is associated with hypermethylation of the promoter area of MGMT gene. (PMID:12720298)
• review on variability and regulation (PMID:12727789)
• decreased MGMT activity in leukocytes from patients with Type 1 and Type 2 diabetes (PMID:12849917)
• In various tumor samples MGMT was lower than MGMT in the normal tissue from the same patient or was even not detectable (PMID:12963053)
• results indicate that it is not necessary for MGMT to actively flip out every base to find damage; they can locate potential lesions by simply capturing a lesioned base that is transiently extrahelical or sensing the unstable nature of a damaged base pair (PMID:14522053)
• Hypermethylation of O6-methylguanine-DNA methyltransferase promoter is associated with colorectal cancer (PMID:14614014)
• Evidence suggests a model for gene silencing of MGMT that is dependent on the epigenetic state in cancer. (PMID:14647440)
• Inactivation of the MGMT gene by promoter methylation was associated with longer survival in glioblastoma patients in a phase II trial treated with temozolomide. (PMID:15041700)
• MGMT codon 178 (and possibly 143) polymorphisms do not appear to markedly affect lung cancer risk in this Caucasian population. (PMID:15140540)
• analysis of DNA binding and nucleotide flipping by the human DNA repair protein AGT (PMID:15221026)
• Polymorphisms in O-6-methylguanine-DNA methyltransferase is associated with lung Neoplasms (PMID:15225156)
• MGMT expression is at least partially influenced by CpG methylation, but may not revert after cancer treatment (PMID:15254699)
• MGMT promoter methylation is not detectable in the investigated samples from acute myeloid leukemia patients. Accordingly, MGMT mRNA expression is found to be normal in all but one case. (PMID:15309527)
• was no relationship between the methylation status of the MGMT promoter and overall survival and response to CENU therapy in glioblastoma patients. (PMID:15332332)
• Frequent promoter hypermethylation and low expression of the MGMT gene is associated with oligodendroglial tumors (PMID:15455350)
• MGMT promoter methylation is associated with malignant astrocytomas (PMID:15455376)
• Histone deacetylation plays a role in MGMT silencing but that CpG methylation has a dominant effect. (PMID:15657354)
• Benzylguanine inactivated MGMT may be linked to cell signaling events, forcing cells into a permanent G2/M arrest in response to the DNA damages induced by BCNU. (PMID:15735757)
• Hypermethylation and protein expression of O6-methylguanine-DNA methyltransferase is associated with uterine cervical lesions (PMID:15785933)
• RASSF1A and MGMT promoter regions are hypermethylated and involved in progression of retinoblastoma (PMID:15799820)
• epigenetic inactivation of MGMT plays an important role in colorectal neoplasia (PMID:15800999)
• silencing of the MGMT gene, a key to DNA repair, is involved in carcinogenesis; we conclude that H3me2K9 and MeCP2 binding are common and more essential for MGMT silencing than DNA hypermethylation or histone deacetylation. (PMID:15809347)
• Cisplatin enhanced sensitivity to ACNU gallbladder cancer cells expressing MGMT both in vitro and in vivo. (PMID:15809756)
• an expressed single nucleotide polymorphism (SNP) and demonstrates that the MGMT alleles are frequently expressed at different levels in peripheral blood mononuclear cells. (PMID:15831531)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mgmt	ENSDARG00000043275
mus_musculus	Mgmt	ENSMUSG00000054612
rattus_norvegicus	Mgmt	ENSRNOG00000016038
drosophila_melanogaster	agt	FBGN0024912
caenorhabditis_elegans		WBGENE00000093

Protein

Protein identifiers

Methylated-DNA–protein-cysteine methyltransferase — P16455 (reviewed: P16455)

Alternative names: 6-O-methylguanine-DNA methyltransferase, O-6-methylguanine-DNA-alkyltransferase

All UniProt accessions (2): P16455, B4DEE8

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the cellular defense against the biological effects of O6-methylguanine (O6-MeG) and O4-methylthymine (O4-MeT) in DNA. Repairs the methylated nucleobase in DNA by stoichiometrically transferring the methyl group to a cysteine residue in the enzyme. This is a suicide reaction: the enzyme is irreversibly inactivated.

Subcellular location. Nucleus.

Cofactor. Binds 1 zinc ion.

Miscellaneous. This enzyme catalyzes only one turnover and therefore is not strictly catalytic. According to one definition, an enzyme is a biocatalyst that acts repeatedly and over many reaction cycles.

Similarity. Belongs to the MGMT family.

RefSeq proteins (1): NP_002403* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001497	MethylDNA_cys_MeTrfase_AS	Active_site
IPR008332	MethylG_MeTrfase_N	Domain
IPR014048	MethylDNA_cys_MeTrfase_DNA-bd	Domain
IPR036217	MethylDNA_cys_MeTrfase_DNAb	Homologous_superfamily
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036631	MGMT_N_sf	Homologous_superfamily

Pfam: PF01035, PF02870

Enzyme classification (BRENDA):

• EC 2.1.1.63 — methylated-DNA-[protein]-cysteine S-methyltransferase (BRENDA: 22 organisms, 52 substrates, 90 inhibitors, 3 Km, 2 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
DNA (CONTAINING 6-O-METHYLGUANINE)	0.0008	1
SNAP-VISTA GREEN	0.01	1

Catalyzed reactions (Rhea), 2 shown:

• a 6-O-methyl-2’-deoxyguanosine in DNA + L-cysteinyl-[protein] = S-methyl-L-cysteinyl-[protein] + a 2’-deoxyguanosine in DNA (RHEA:24000)
• a 4-O-methyl-thymidine in DNA + L-cysteinyl-[protein] = a thymidine in DNA + S-methyl-L-cysteinyl-[protein] (RHEA:53428)

UniProt features (50 total): mutagenesis site 11, binding site 10, sequence variant 10, helix 8, strand 5, modified residue 2, chain 1, active site 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

23 structures.

PDB	Method	Resolution (Å)
1QNT	X-RAY DIFFRACTION	1.9
1EH6	X-RAY DIFFRACTION	2
1EH7	X-RAY DIFFRACTION	2
9QF2	ELECTRON MICROSCOPY	2.42
1EH8	X-RAY DIFFRACTION	2.5
28OP	ELECTRON MICROSCOPY	2.7
9QEY	ELECTRON MICROSCOPY	2.74
9QFB	ELECTRON MICROSCOPY	2.74
9QFQ	ELECTRON MICROSCOPY	2.76
1YFH	X-RAY DIFFRACTION	3.01
9DI0	ELECTRON MICROSCOPY	3.1
9QFE	ELECTRON MICROSCOPY	3.12
9QFW	ELECTRON MICROSCOPY	3.16
1T38	X-RAY DIFFRACTION	3.2
1T39	X-RAY DIFFRACTION	3.3
8RU2	ELECTRON MICROSCOPY	3.49
9QFG	ELECTRON MICROSCOPY	3.49
8RGH	ELECTRON MICROSCOPY	3.9
9QFK	ELECTRON MICROSCOPY	3.99
8RGG	ELECTRON MICROSCOPY	4
8RTY	ELECTRON MICROSCOPY	6.25
9HHL	ELECTRON MICROSCOPY	6.53
9TAY	ELECTRON MICROSCOPY	15.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P16455-F1	86.86	0.76

Functional residue map

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

Catalytic / active sites (1): 145 (nucleophile; methyl group acceptor)

Ligand- & substrate-binding residues (10): 128; 151; 5; 24; 29; 85; 95; 114; 115; 123

Post-translational modifications (2): 14, 201

Mutagenesis-validated functional residues (11):

Position	Phenotype
114	decreases activity towards methylated dna over 1000-fold. slightly reduced reactivity with o6-benzylguanine.
114	loss of dna repair activity. slightly reduced reactivity with o6-benzylguanine.
128	decreases activity towards methylated dna over 1000-fold. no effect on reactivity with o6-benzylguanine.
128	loss of dna repair activity.
128	slightly reduced dna repair activity.
138	decreased reactivity with o6-benzylguanine.
140	decreased reactivity with o6-benzylguanine.
145	loss of dna repair activity.
156	decreased reactivity with o6-benzylguanine.
158	reduced dna repair activity. decreased reactivity with o6-benzylguanine.
158	slightly reduced dna repair activity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-5657655	MGMT-mediated DNA damage reversal
R-HSA-73894	DNA Repair
R-HSA-73942	DNA Damage Reversal

MSigDB gene sets: 154 (showing top): GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, ENK_UV_RESPONSE_KERATINOCYTE_UP, LI_PROSTATE_CANCER_EPIGENETIC, KAUFFMANN_DNA_REPAIR_GENES, GOBP_REGULATION_OF_DNA_REPAIR, KOKKINAKIS_METHIONINE_DEPRIVATION_96HR_UP, OHM_METHYLATED_IN_ADULT_CANCERS, BROWNE_HCMV_INFECTION_14HR_DN, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, KOKKINAKIS_METHIONINE_DEPRIVATION_48HR_UP, GOBP_DNA_DAMAGE_RESPONSE, GOBP_POSITIVE_REGULATION_OF_DNA_REPAIR, BROWNE_HCMV_INFECTION_24HR_DN, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_STRESS, REACTOME_DNA_REPAIR

GO Biological Process (6): DNA repair (GO:0006281), DNA alkylation repair (GO:0006307), methylation (GO:0032259), negative regulation of apoptotic process (GO:0043066), positive regulation of double-strand break repair (GO:2000781), DNA damage response (GO:0006974)

GO Molecular Function (7): DNA binding (GO:0003677), methylated-DNA-[protein]-cysteine S-methyltransferase activity (GO:0003908), methyltransferase activity (GO:0008168), DNA-methyltransferase activity (GO:0009008), metal ion binding (GO:0046872), catalytic activity (GO:0003824), transferase activity (GO:0016740)

GO Cellular Component (3): nucleus (GO:0005634), nucleoplasm (GO:0005654), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
DNA Damage Reversal	1
DNA Repair	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
DNA metabolic process	1
DNA damage response	1
DNA repair	1
metabolic process	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
double-strand break repair	1
positive regulation of DNA repair	1
regulation of double-strand break repair	1
cellular response to stress	1
nucleic acid binding	1
S-methyltransferase activity	1
protein methyltransferase activity	1
transferase activity, transferring one-carbon groups	1
methyltransferase activity	1
catalytic activity, acting on DNA	1
cation binding	1
molecular_function	1
catalytic activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1

Protein interactions and networks

STRING

2746 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MGMT	IDH1	O75874	930
MGMT	IDH2	P48735	882
MGMT	CDKN2A	P42771	876
MGMT	RASSF1	Q9NS23	868
MGMT	MLH1	P40692	853
MGMT	EGFR	P00533	822
MGMT	MPG	P29372	814
MGMT	PMS2	P54278	789
MGMT	DAPK1	P53355	783
MGMT	HIC1	Q14526	780
MGMT	TP53	P04637	770
MGMT	MSH6	P52701	752
MGMT	XRCC1	P18887	729
MGMT	ATRX	P46100	729
MGMT	GSTP1	P09211	719

IntAct

4 interactions, top by confidence:

A	B	Type	Score
PAK4	SNRPE	psi-mi:“MI:0914”(association)	0.350
	POLRMT	psi-mi:“MI:0914”(association)	0.350
	MGMT	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (103): FANCA (Affinity Capture-Luminescence), PCNA (Affinity Capture-Western), MGMT (Affinity Capture-Western), PCNA (Reconstituted Complex), CDKN1A (Affinity Capture-Western), CDK2 (Affinity Capture-Western), MGMT (Affinity Capture-Western), DTL (Affinity Capture-Western), MGMT (Affinity Capture-MS), MGMT (Proximity Label-MS), MGMT (Affinity Capture-MS), MGMT (Biochemical Activity), MGMT (Biochemical Activity), MGMT (Biochemical Activity), MGMT (Biochemical Activity)

ESM2 similar proteins: A0KPI3, A1AG60, A4Q8H2, A4SIJ4, A4WEX0, A4XXY7, A5WDY2, A6TEH4, A7N3Z0, A8AQ40, A8G925, B1LFQ6, B1XGW7, B5YS45, B7M063, B7MB76, B7NDD9, B7NKM4, B7UJ50, C4ZSP6, C6DF27, O10332, P09135, P0AFP2, P0AFP3, P16455, P24528, P26187, P33353, P45472, P58700, Q0HMP1, Q0TCV4, Q121Q5, Q2NVZ9, Q2NW13, Q2P644, Q32BH8, Q4UXR7, Q66EU5

Diamond homologs: A3LZM4, A4YH39, A5E7M8, A6B4U8, A6ZXD3, C3MKT6, C3MUC6, C3N1B4, C3N9B4, C3NMY2, C4KKV8, C5A3L5, C9RE37, F0LIT8, F4HK38, O26715, O27970, O59499, O74023, O93728, P06134, P0A2U0, P0A2U1, P0A697, P0AFH0, P0AFH1, P11742, P16455, P19220, P24528, P26186, P26187, P26188, P26189, P44687, P52982, P9WJW4, P9WJW5, Q46EW4, Q4J9C6

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
MECP2	“down-regulates quantity by repression”	MGMT	“transcriptional regulation”
MBD1	“down-regulates quantity by repression”	MGMT	“transcriptional regulation”
CHAF1A	“down-regulates quantity by repression”	MGMT	“transcriptional regulation”
CHAF1B	“down-regulates quantity by repression”	MGMT	“transcriptional regulation”
TP53	“down-regulates quantity by repression”	MGMT	“transcriptional regulation”
IFNB1	“down-regulates quantity by repression”	MGMT	“transcriptional regulation”

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	39
Likely benign	6
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
812926	NC_000010.10:g.129942146_132848717del	Likely pathogenic

SpliceAI

4494 predictions. Top by Δscore:

Variant	Effect	Δscore
10:129536237:TTAGG:T	acceptor_loss	1.0000
10:129536238:TA:T	acceptor_loss	1.0000
10:129536239:A:AG	acceptor_gain	1.0000
10:129536239:AG:A	acceptor_gain	1.0000
10:129536240:G:GT	acceptor_gain	1.0000
10:129536240:GG:G	acceptor_gain	1.0000
10:129536240:GGT:G	acceptor_gain	1.0000
10:129536240:GGTA:G	acceptor_gain	1.0000
10:129536240:GGTAC:G	acceptor_gain	1.0000
10:129536373:GCTGA:G	donor_gain	1.0000
10:129536374:C:G	donor_gain	1.0000
10:129536374:CTGA:C	donor_gain	1.0000
10:129536375:TGA:T	donor_gain	1.0000
10:129536376:GA:G	donor_gain	1.0000
10:129536376:GAG:G	donor_gain	1.0000
10:129536377:AG:A	donor_loss	1.0000
10:129536378:G:GG	donor_gain	1.0000
10:129536379:TAAG:T	donor_loss	1.0000
10:129536382:G:GG	donor_gain	1.0000
10:129759342:G:GG	donor_gain	1.0000
10:129467297:G:GG	donor_gain	0.9900
10:129467297:G:T	donor_loss	0.9900
10:129467299:GA:G	donor_loss	0.9900
10:129529610:G:T	donor_gain	0.9900
10:129536230:T:G	acceptor_gain	0.9900
10:129536380:AA:A	donor_loss	0.9900
10:129538255:A:G	donor_gain	0.9900
10:129538294:G:GG	donor_gain	0.9900
10:129595849:GAGGA:G	donor_gain	0.9900
10:129707893:A:AG	acceptor_gain	0.9900

AlphaMissense

1308 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:129766868:G:C	K165N	0.994
10:129766868:G:T	K165N	0.994
10:129759207:T:C	F94L	0.991
10:129759209:C:A	F94L	0.991
10:129759209:C:G	F94L	0.991
10:129766813:G:T	R147I	0.991
10:129766814:A:C	R147S	0.990
10:129766814:A:T	R147S	0.990
10:129759336:A:G	N137D	0.988
10:129766813:G:C	R147T	0.988
10:129759338:T:A	N137K	0.987
10:129759338:T:G	N137K	0.987
10:129536292:A:C	S14R	0.986
10:129536294:C:A	S14R	0.986
10:129536294:C:G	S14R	0.986
10:129759319:G:A	G131E	0.986
10:129766806:T:C	C145R	0.986
10:129707974:T:G	Y69D	0.985
10:129766809:C:G	H146D	0.984
10:129766795:T:A	I141N	0.983
10:129707966:T:C	L66P	0.982
10:129707978:T:C	F70S	0.982
10:129759280:C:A	A118E	0.982
10:129759267:T:C	Y114H	0.981
10:129759277:T:C	L117S	0.980
10:129766795:T:C	I141T	0.980
10:129766876:T:C	L168P	0.980
10:129759279:G:C	A118P	0.979
10:129766807:G:A	C145Y	0.979
10:129766888:A:T	E172V	0.979

dbSNP variants (sampled 300 via entrez): RS1000003241 (10:129613959 A>C,G), RS1000006433 (10:129490998 T>C), RS1000011052 (10:129732631 T>G), RS1000025737 (10:129763402 G>T), RS1000037072 (10:129637739 G>C,T), RS1000038397 (10:129649306 T>C,G), RS1000039534 (10:129755395 G>C), RS1000060148 (10:129506412 C>T), RS1000066397 (10:129748573 C>A), RS1000074420 (10:129690711 A>G), RS1000095108 (10:129760107 G>A,C), RS1000097746 (10:129479518 GA>G), RS1000099561 (10:129683775 G>A), RS1000100499 (10:129502645 C>G), RS1000104262 (10:129723142 G>A,C)

Disease associations

OMIM: gene MIM:156569 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): paroxysmal dyskinesia (MONDO:0015427)

Orphanet (1): Paroxysmal dyskinesia (Orphanet:1431)

HPO phenotypes

11 total (11 of 11 shown, HPO-id order):

HPO	Term
HP:0000488	Retinopathy
HP:0000958	Dry skin
HP:0001480	Freckling
HP:0001595	Abnormal hair morphology
HP:0002071	Abnormality of extrapyramidal motor function
HP:0002861	Melanoma
HP:0002894	Neoplasm of the pancreas
HP:0003764	Nevus
HP:0006753	Neoplasm of the stomach
HP:0100013	Neoplasm of the breast
HP:0100763	Abnormality of the lymphatic system

GWAS associations

23 associations (top):

Study	Trait	p-value
GCST001730_1	Response to temozolomide	1.000000e-08
GCST001754_1	Waist-to-hip circumference ratio (ever vs never smoking interaction)	9.000000e-07
GCST002119_27	Metabolite levels (X-11787)	5.000000e-06
GCST002740_23	Inflammatory skin disease	6.000000e-07
GCST002817_24	Alzheimer’s disease in APOE e4- carriers	8.000000e-06
GCST002935_26	Lead levels	9.000000e-06
GCST003031_3	MGMT methylation in smokers	4.000000e-31
GCST003854_20	Gut microbiota (functional units)	3.000000e-08
GCST005235_19	Hand grip strength	1.000000e-10
GCST005580_257	Intraocular pressure	2.000000e-10
GCST005830_24	Hand grip strength	1.000000e-13
GCST006979_615	Heel bone mineral density	8.000000e-21
GCST007537_2	Modic changes	9.000000e-06
GCST007576_321	Chronotype	8.000000e-09
GCST007630_5	Drug experimentation measurement	2.000000e-06
GCST007740_25	Iris color (a* coordinate)	7.000000e-06
GCST007741_4	Iris color (b* coordinate)	8.000000e-07
GCST008465_4	Anorexia nervosa	2.000000e-08
GCST008529_55	Tea consumption	1.000000e-06
GCST009391_1057	Metabolite levels	5.000000e-06
GCST010988_455	Adult body size	7.000000e-09
GCST011742_32	Triglyceride levels in HIV infection	3.000000e-06
GCST011743_81	HDL cholesterol levels in HIV infection	4.000000e-06

EFO canonical traits (14, from GWAS)

EFO ID	Trait name
EFO:0004343	waist-hip ratio
EFO:0005276	hydroxy-leucine measurement
EFO:0006959	gene methylation measurement
EFO:0007874	gut microbiome measurement
EFO:0006941	grip strength measurement
EFO:0004695	intraocular pressure measurement
EFO:0009270	heel bone mineral density
EFO:0008328	chronotype measurement
EFO:0007010	drug use measurement
EFO:0009764	eye colour measurement
EFO:0010091	tea consumption measurement
EFO:0010363	lysophosphatidylcholine 20:4 measurement
EFO:0004530	triglyceride measurement
EFO:0004612	high density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2864 (SINGLE PROTEIN), CHEMBL4742274 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 7,131 (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
CHEMBL407874	6-O-BENZYLGUANINE	3	6,988
CHEMBL339133	LOMEGUATRIB	2	143

Clinical evidence (CIViC)

Drug × variant × indication: 9 predictive associations from 10 curated evidence items; also 3 prognostic.

Variant	Therapy	Indication	Effect	Level	CIViC
MGMT Promoter Methylation	Temozolomide	Glioblastoma	Sensitivity/Response	CIViC A	EID307
MGMT Promoter Methylation	Lomustine + Temozolomide	Glioblastoma	Sensitivity/Response	CIViC A	EID7303
MGMT Underexpression	Temozolomide	Glioblastoma	Sensitivity/Response	CIViC B	EID2899 +1
MGMT Promoter Methylation	Carmustine	Glioblastoma	Sensitivity/Response	CIViC B	EID308
MGMT RS16906252	Temozolomide	Glioblastoma	Sensitivity/Response	CIViC B	EID822
MGMT Underexpression	Temozolomide	High Grade Glioma	Sensitivity/Response	CIViC B	EID2901
MGMT Underexpression	Temozolomide	Oligodendroglioma	Sensitivity/Response	CIViC B	EID2902
MGMT Underexpression	Temozolomide	Neuroendocrine Tumor	Sensitivity/Response	CIViC B	EID2904
MGMT Promoter Methylation	O6-Benzylguanine	Glioblastoma	Sensitivity/Response	CIViC E	EID309

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

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2308321	MGMT		0.00	0
rs2308327	MGMT		0.00	0
rs4751104	MGMT		0.00	0

ChEMBL bioactivities

72 potent at pChembl≥5 of 92 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.52	IC50	3	nM	LOMEGUATRIB
8.52	IC50	3	nM	CHEMBL337677
8.30	IC50	5	nM	CHEMBL146769
8.05	IC50	9	nM	CHEMBL485756
8.05	IC50	9	nM	LOMEGUATRIB
8.00	IC50	10	nM	CHEMBL146769
7.75	IC50	18	nM	CHEMBL151579
7.62	Ki	24	nM	CHEMBL4454794
7.60	IC50	25	nM	CHEMBL2171205
7.52	IC50	30	nM	CHEMBL131510
7.52	IC50	30	nM	CHEMBL129850
7.52	IC50	30	nM	CHEMBL151579
7.50	IC50	32	nM	CHEMBL336947
7.48	IC50	33	nM	CHEMBL345550
7.42	IC50	38	nM	CHEMBL333928
7.41	IC50	39	nM	6-O-BENZYLGUANINE
7.40	IC50	40	nM	CHEMBL151495
7.40	IC50	40	nM	6-O-BENZYLGUANINE
7.30	IC50	50	nM	CHEMBL151495
7.29	IC50	51	nM	CHEMBL149722
7.24	IC50	58	nM	6-O-BENZYLGUANINE
7.22	IC50	60	nM	CHEMBL345550
7.16	IC50	70	nM	CHEMBL150324
7.10	IC50	80	nM	CHEMBL146768
7.07	IC50	86	nM	CHEMBL2171202
7.05	IC50	90	nM	CHEMBL150918
7.00	IC50	100	nM	6-O-BENZYLGUANINE
6.92	IC50	120	nM	CHEMBL146768
6.92	IC50	120	nM	CHEMBL151785
6.89	IC50	130	nM	CHEMBL146734
6.89	IC50	130	nM	CHEMBL71484
6.75	IC50	180	nM	6-O-BENZYLGUANINE
6.70	IC50	200	nM	CHEMBL151552
6.70	IC50	200	nM	CHEMBL146734
6.70	IC50	200	nM	CHEMBL151785
6.70	IC50	200	nM	CHEMBL405259
6.66	IC50	220	nM	CHEMBL150427
6.66	IC50	220	nM	CHEMBL342497
6.64	IC50	230	nM	CHEMBL150918
6.64	IC50	230	nM	CHEMBL358907
6.60	IC50	250	nM	CHEMBL336215
6.60	IC50	250	nM	CHEMBL151552
6.50	IC50	320	nM	CHEMBL1683172
6.46	IC50	350	nM	CHEMBL150427
6.46	IC50	350	nM	CHEMBL356396
6.41	IC50	390	nM	CHEMBL405259
6.37	IC50	430	nM	CHEMBL342497
6.35	IC50	450	nM	CHEMBL134079
6.35	IC50	450	nM	CHEMBL339016
6.26	IC50	550	nM	CHEMBL439608

PubChem BioAssay actives

72 with measured affinity, of 452 total; 49 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
6-[(4-bromothiophen-2-yl)methoxy]-7H-purin-2-amine	579768: Inactivation of human O-6-methylguanine-DNA methyltransferase assessed as [3H]methylated protein formation by liquid scintillation counting in presence of [3H]methylated calf thymus DNA	ic50	0.0030	uM
6-thiophen-2-yloxy-7H-purin-2-amine	31150: Inhibition of AGT activity to 50% of control rate in HT-29 cell extract	ic50	0.0030	uM
6-[(5-bromothiophen-2-yl)methoxy]-6,7-dihydro-3H-purin-2-amine	147467: O6-Alkylguanine-DNA Alkyltransferase-Inactivating Activity (Concentration of inactivator required to produce 50% reduction in ATPase activity)	ic50	0.0050	uM
6-[[3-(aminomethyl)phenyl]methoxy]-7H-purin-2-amine	702534: Inhibition of AGT in human HL60 cells assessed as AGT levels using [3H]AGT after 2 hrs	ic50	0.0090	uM
6-(thiophen-2-ylmethoxy)-6,7-dihydro-3H-purin-2-amine	147467: O6-Alkylguanine-DNA Alkyltransferase-Inactivating Activity (Concentration of inactivator required to produce 50% reduction in ATPase activity)	ic50	0.0180	uM
1-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethyl]-5-(chloromethyl)triazole	1553451: Inhibition of MGMT (unknown origin)	ki	0.0240	uM
6-[[3-[(dimethylamino)methyl]phenyl]methoxy]-7H-purin-2-amine	702534: Inhibition of AGT in human HL60 cells assessed as AGT levels using [3H]AGT after 2 hrs	ic50	0.0250	uM
(2S,4R,5S)-2-[10-[2-amino-6-[(4-bromothiophen-2-yl)methoxy]purin-9-yl]decoxy]-6-(hydroxymethyl)oxane-3,4,5-triol	106501: In vitro inhibition of MGMT using cell free extracts from HeLa S3 cells	ic50	0.0300	uM
(2S,4R,5S)-2-[12-[2-amino-6-[(4-bromothiophen-2-yl)methoxy]purin-9-yl]dodecoxy]-6-(hydroxymethyl)oxane-3,4,5-triol	106501: In vitro inhibition of MGMT using cell free extracts from HeLa S3 cells	ic50	0.0300	uM
(2S,4R,5S)-2-[8-[2-amino-6-[(4-bromothiophen-2-yl)methoxy]purin-9-yl]octoxy]-6-(hydroxymethyl)oxane-3,4,5-triol	106501: In vitro inhibition of MGMT using cell free extracts from HeLa S3 cells	ic50	0.0320	uM
6-(1,3-thiazol-5-ylmethoxy)-6,7-dihydro-3H-purin-2-amine	147467: O6-Alkylguanine-DNA Alkyltransferase-Inactivating Activity (Concentration of inactivator required to produce 50% reduction in ATPase activity)	ic50	0.0330	uM
7-phenylmethoxy-2H-triazolo[4,5-d]pyrimidin-5-amine	106501: In vitro inhibition of MGMT using cell free extracts from HeLa S3 cells	ic50	0.0380	uM
6-phenylmethoxy-7H-purin-2-amine	702534: Inhibition of AGT in human HL60 cells assessed as AGT levels using [3H]AGT after 2 hrs	ic50	0.0390	uM
6-[(2-chloro-4-pyridinyl)methoxy]-6,7-dihydro-3H-purin-2-amine	147467: O6-Alkylguanine-DNA Alkyltransferase-Inactivating Activity (Concentration of inactivator required to produce 50% reduction in ATPase activity)	ic50	0.0400	uM
6-[(4-fluorophenyl)methoxy]-5-nitrosopyrimidine-2,4-diamine	147600: In vitro inhibitory activity against human O6-alkylguanine-DNA alkyltransferase (AGAT)	ic50	0.0510	uM
6-(1,2-thiazol-4-ylmethoxy)-6,7-dihydro-3H-purin-2-amine	147467: O6-Alkylguanine-DNA Alkyltransferase-Inactivating Activity (Concentration of inactivator required to produce 50% reduction in ATPase activity)	ic50	0.0700	uM
6-(furan-2-ylmethoxy)-6,7-dihydro-3H-purin-2-amine	147467: O6-Alkylguanine-DNA Alkyltransferase-Inactivating Activity (Concentration of inactivator required to produce 50% reduction in ATPase activity)	ic50	0.0800	uM
N-[[3-[(2-amino-7H-purin-6-yl)oxymethyl]phenyl]methyl]acetamide	702534: Inhibition of AGT in human HL60 cells assessed as AGT levels using [3H]AGT after 2 hrs	ic50	0.0860	uM
6-([1,3]dioxolo[4,5-b]pyridin-6-ylmethoxy)-6,7-dihydro-3H-purin-2-amine	147468: O6-Alkylguanine-DNA Alkyltransferase-Inactivating Activity in Raji cells (Concentration of inactivator required to produce 50% reduction in ATPase activity)	ic50	0.0900	uM
6-[(6-chloro-3-pyridinyl)methoxy]-6,7-dihydro-3H-purin-2-amine	147468: O6-Alkylguanine-DNA Alkyltransferase-Inactivating Activity in Raji cells (Concentration of inactivator required to produce 50% reduction in ATPase activity)	ic50	0.1200	uM
5-nitroso-6-phenylmethoxypyrimidine-2,4-diamine	147600: In vitro inhibitory activity against human O6-alkylguanine-DNA alkyltransferase (AGAT)	ic50	0.1300	uM
6-(pyridin-4-ylmethoxy)-6,7-dihydro-3H-purin-2-amine	147467: O6-Alkylguanine-DNA Alkyltransferase-Inactivating Activity (Concentration of inactivator required to produce 50% reduction in ATPase activity)	ic50	0.1300	uM
6-[(5-bromo-3-pyridinyl)methoxy]-6,7-dihydro-3H-purin-2-amine	147468: O6-Alkylguanine-DNA Alkyltransferase-Inactivating Activity in Raji cells (Concentration of inactivator required to produce 50% reduction in ATPase activity)	ic50	0.2000	uM
6-(cyclopenten-1-ylmethoxy)-7H-purin-2-amine	31154: concentration required to reduce AGT activity to 50% of control rate in intact HT-29 human colorectal carcinoma cells	ic50	0.2000	uM
6-(pyridin-3-ylmethoxy)-6,7-dihydro-3H-purin-2-amine	147468: O6-Alkylguanine-DNA Alkyltransferase-Inactivating Activity in Raji cells (Concentration of inactivator required to produce 50% reduction in ATPase activity)	ic50	0.2200	uM
6-(1,3-oxazol-5-ylmethoxy)-6,7-dihydro-3H-purin-2-amine	147468: O6-Alkylguanine-DNA Alkyltransferase-Inactivating Activity in Raji cells (Concentration of inactivator required to produce 50% reduction in ATPase activity)	ic50	0.2200	uM
5-nitroso-6-(pyridin-4-ylmethoxy)pyrimidine-2,4-diamine	147600: In vitro inhibitory activity against human O6-alkylguanine-DNA alkyltransferase (AGAT)	ic50	0.2300	uM
(2S,4R,5S)-2-[4-[2-amino-6-[(4-bromothiophen-2-yl)methoxy]purin-9-yl]but-2-ynoxy]-6-(hydroxymethyl)oxane-3,4,5-triol	106501: In vitro inhibition of MGMT using cell free extracts from HeLa S3 cells	ic50	0.2500	uM
6-[(4-bromothiophen-2-yl)methoxy]-5-nitropyrimidine-2,4-diamine	579768: Inactivation of human O-6-methylguanine-DNA methyltransferase assessed as [3H]methylated protein formation by liquid scintillation counting in presence of [3H]methylated calf thymus DNA	ic50	0.3200	uM
6-[(4-fluorophenyl)methoxy]-5-nitropyrimidine-2,4-diamine	147600: In vitro inhibitory activity against human O6-alkylguanine-DNA alkyltransferase (AGAT)	ic50	0.3500	uM
(2S,4R,5S)-2-[6-[2-amino-6-[(4-bromothiophen-2-yl)methoxy]purin-9-yl]hexoxy]-6-(hydroxymethyl)oxane-3,4,5-triol	106501: In vitro inhibition of MGMT using cell free extracts from HeLa S3 cells	ic50	0.4500	uM
(2S,4R,5S)-2-[4-[2-amino-6-[(4-bromothiophen-2-yl)methoxy]purin-9-yl]butoxy]-6-(hydroxymethyl)oxane-3,4,5-triol	106501: In vitro inhibition of MGMT using cell free extracts from HeLa S3 cells	ic50	0.4500	uM
6-(cyclobuten-1-ylmethoxy)-7H-purin-2-amine	31150: Inhibition of AGT activity to 50% of control rate in HT-29 cell extract	ic50	0.5500	uM
(2R,4S,5R)-2-[2-[2-amino-6-[(4-bromothiophen-2-yl)methoxy]purin-9-yl]ethoxy]-6-(hydroxymethyl)oxane-3,4,5-triol	106501: In vitro inhibition of MGMT using cell free extracts from HeLa S3 cells	ic50	0.6800	uM
4-[(4-bromothiophen-2-yl)methoxy]-6-morpholin-4-yl-5-nitropyrimidin-2-amine	579768: Inactivation of human O-6-methylguanine-DNA methyltransferase assessed as [3H]methylated protein formation by liquid scintillation counting in presence of [3H]methylated calf thymus DNA	ic50	1.0000	uM
5-nitro-6-phenylmethoxypyrimidine-2,4-diamine	147600: In vitro inhibitory activity against human O6-alkylguanine-DNA alkyltransferase (AGAT)	ic50	1.3000	uM
6-[(1-oxidopyridin-1-ium-3-yl)methoxy]-6,7-dihydro-3H-purin-2-amine	147467: O6-Alkylguanine-DNA Alkyltransferase-Inactivating Activity (Concentration of inactivator required to produce 50% reduction in ATPase activity)	ic50	1.4000	uM
5-nitro-6-(pyridin-3-ylmethoxy)pyrimidine-2,4-diamine	147600: In vitro inhibitory activity against human O6-alkylguanine-DNA alkyltransferase (AGAT)	ic50	1.6000	uM
6-(cyclohexen-1-ylmethoxy)-7H-purin-2-amine	31150: Inhibition of AGT activity to 50% of control rate in HT-29 cell extract	ic50	1.6000	uM
5-nitro-6-(pyridin-4-ylmethoxy)pyrimidine-2,4-diamine	147600: In vitro inhibitory activity against human O6-alkylguanine-DNA alkyltransferase (AGAT)	ic50	1.9000	uM
(2R,4S,5R)-2-[2-(5-amino-7-phenylmethoxytriazolo[4,5-d]pyrimidin-3-yl)ethoxy]-6-(hydroxymethyl)oxane-3,4,5-triol	106501: In vitro inhibition of MGMT using cell free extracts from HeLa S3 cells	ic50	2.0000	uM
6-[(3-fluorophenyl)methoxy]-5-nitropyrimidine-2,4-diamine	147600: In vitro inhibitory activity against human O6-alkylguanine-DNA alkyltransferase (AGAT)	ic50	2.5000	uM
6-[[(4R)-4-prop-1-en-2-ylcyclohexen-1-yl]methoxy]-7H-purin-2-amine	31150: Inhibition of AGT activity to 50% of control rate in HT-29 cell extract	ic50	2.6000	uM
6-prop-2-enoxy-7H-purin-2-amine	31155: concentration required to reduce AGT activity to 50% of control rate in intact HT-29 human colorectal carcinoma cells.	ic50	2.7000	uM
4-N-[4-(4-aminoanilino)phenyl]-6-[(4-bromothiophen-2-yl)methoxy]-5-nitropyrimidine-2,4-diamine	579768: Inactivation of human O-6-methylguanine-DNA methyltransferase assessed as [3H]methylated protein formation by liquid scintillation counting in presence of [3H]methylated calf thymus DNA	ic50	4.7000	uM
[4-[[2-amino-6-[(4-bromothiophen-2-yl)methoxy]-5-nitropyrimidin-4-yl]amino]phenyl]-(4-aminophenyl)methanone	579768: Inactivation of human O-6-methylguanine-DNA methyltransferase assessed as [3H]methylated protein formation by liquid scintillation counting in presence of [3H]methylated calf thymus DNA	ic50	5.7000	uM
6-(pyridin-2-ylmethoxy)-6,7-dihydro-3H-purin-2-amine	147468: O6-Alkylguanine-DNA Alkyltransferase-Inactivating Activity in Raji cells (Concentration of inactivator required to produce 50% reduction in ATPase activity)	ic50	6.0000	uM
6-[(3-methylimidazol-4-yl)methoxy]-6,7-dihydro-3H-purin-2-amine	147467: O6-Alkylguanine-DNA Alkyltransferase-Inactivating Activity (Concentration of inactivator required to produce 50% reduction in ATPase activity)	ic50	8.5000	uM
6-(2-methylprop-2-enoxy)-7H-purin-2-amine	31155: concentration required to reduce AGT activity to 50% of control rate in intact HT-29 human colorectal carcinoma cells.	ic50	9.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Carmustine	increases alkylation, affects response to substance, decreases response to substance, increases response to substance, decreases reaction (+3 more)	34
O(6)-benzylguanine	increases expression, affects binding, affects cotreatment, affects metabolic processing, decreases activity (+6 more)	32
Temozolomide	affects response to substance, decreases response to substance, increases expression, increases reaction, affects reaction (+5 more)	20
Decitabine	affects binding, increases reaction, decreases methylation, affects cotreatment, decreases expression (+2 more)	5
Benzo(a)pyrene	decreases expression, affects methylation	5
Cisplatin	decreases activity, decreases expression, decreases response to substance	5
Dacarbazine	decreases activity, decreases expression, affects response to substance, decreases response to substance	5
Methylnitrosourea	increases alkylation, decreases response to substance, affects cotreatment	5
bisphenol A	affects binding, affects folding, increases reaction, affects cotreatment, increases methylation (+1 more)	4
Nimustine	decreases response to substance, increases reaction, affects cotreatment, increases expression, decreases activity (+2 more)	4
Ethylene Dibromide	affects binding, decreases activity, affects metabolic processing, increases activity, increases response to substance	4
Aflatoxin B1	affects expression, decreases expression, decreases methylation, increases methylation	4
sodium arsenite	decreases expression	3
mitozolomide	decreases response to substance	3
fotemustine	decreases response to substance	3
O(6)-(4-bromothenyl)guanine	affects cotreatment, decreases response to substance, decreases reaction, decreases activity	3
laromustine	decreases activity, decreases response to substance	3
Guanine	decreases activity, decreases methylation	3
Methyl Methanesulfonate	increases alkylation, increases response to substance, decreases response to substance	3
Vincristine	affects cotreatment, affects response to substance, decreases response to substance	3
epigallocatechin gallate	decreases methylation, increases expression	2
Irinotecan	decreases expression, increases response to substance	2
Alkylating Agents	decreases response to substance	2
Arsenic	affects expression, affects methylation	2
Azacitidine	decreases methylation, increases expression	2
Curcumin	decreases expression, increases activity, increases expression, decreases activity	2
Cyclophosphamide	decreases expression, decreases response to substance	2
Dexamethasone	decreases response to substance, increases reaction, increases expression, affects cotreatment	2
Fluorouracil	decreases expression, decreases response to substance, decreases reaction	2
Lomustine	decreases response to substance, affects cotreatment, affects response to substance	2

ChEMBL screening assays

86 unique, capped per target: 84 binding, 2 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1687568	Binding	Inactivation of human O-6-methylguanine-DNA methyltransferase assessed as [3H]methylated protein formation by liquid scintillation counting in presence of [3H]methylated calf thymus DNA	Towards more specific O6-methylguanine-DNA methyltransferase (MGMT) inactivators. — Bioorg Med Chem
CHEMBL4329748	ADMET	Inhibition of recombinant human N-terminal His-tagged MGMT (1 to 207 residues) expressed in Escherichia coli using O-6-benzylguanine as substrate after 30 mins by LC-MS analysis	Potent Triazolopyridine Myeloperoxidase Inhibitors. — ACS Med Chem Lett

Cellosaurus cell lines

28 cell lines: 15 cancer cell line, 11 induced pluripotent stem cell, 1 embryonic stem cell, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1330	KM-H2	Cancer cell line	Male
CVCL_A5QV	WAe001-A-56	Embryonic stem cell	Male
CVCL_B7FL	U-2 OS-CRISPR-NUP96-SNAP clone #33	Cancer cell line	Female
CVCL_B7FM	U-2 OS-ZFN-SNAP-Nup107 no.294	Cancer cell line	Female
CVCL_B8KF	Abcam HCT 116 MGMT KO	Cancer cell line	Male
CVCL_B8YU	Abcam MCF-7 MGMT KO	Cancer cell line	Female
CVCL_B9MP	Abcam A-549 MGMT KO	Cancer cell line	Male
CVCL_E0I0	Ubigene HeLa MGMT KO	Cancer cell line	Female
CVCL_E3C8	A53T-1A	Induced pluripotent stem cell	Female
CVCL_E3C9	A53T-1C	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06701851	Not specified	RECRUITING	Neural Correlates of Movement Disorders Associated With PRRT2 Related Paroxysmal Kinesigenic Dyskinesia - an Ancillary Study of AMEDYST Research