m6A-centered Crosstalk Information

Mechanism of Crosstalk between m6A Modification and Epigenetic Regulation
Crosstalk ID
M6ACROT00127
 [1], [2], [3], [4]
m6A modification ADAR1 ADAR1 METTL3 Methylation : m6A sites Direct Enhancement RNA modification Mdm2 Mdm2 ADAR Methylation : modification sites
m6A Modification:
m6A Regulator Methyltransferase-like 3 (METTL3) WRITER
 Regulator Info 
m6A Target Interferon-inducible protein 4 (ADAR1)
 Targert Gene 
Epigenetic Regulation that have Cross-talk with This m6A Modification:
Epigenetic Regulation Type RNA modification (RNAMod)  >> Adenosine-to-Inosine editing (A-to-I)
Epigenetic Regulator Interferon-inducible protein 4 (ADAR1) WRITER View Details
Regulated Target E3 ubiquitin-protein ligase Mdm2 (Mdm2) View Details
Crosstalk Relationship m6A  →  A-to-I Enhancement
Crosstalk Mechanism m6A modification directly impacts RNA modification through modulating the expression level of RNA modification regulator
Crosstalk Summary METTL3 methylates Interferon-inducible protein 4 (ADAR1) mRNA, thereby enhancing its protein expression, which subsequently promotes ADAR mediated A-to-I RNA editing of the E3 ubiquitin-protein ligase Mdm2 (Mdm2) transcript.
Responsed Drug RG7388
 Drug Info 
Pathway Response mRNA surveillance pathway hsa03015
RNA degradation hsa03018
Cell Process RNA stability
In-vitro Model
 MGG8 Glioblastoma Homo sapiens CVCL_D1H4
U-87MG ATCC Glioblastoma Homo sapiens CVCL_0022
U-118MG Astrocytoma Homo sapiens CVCL_0633
WI-38 Normal Homo sapiens CVCL_0579
HEK293 Normal Homo sapiens CVCL_0045
HEK293T Normal Homo sapiens CVCL_0063
K-562 Chronic myelogenous leukemia Homo sapiens CVCL_0004
Full List of Potential Compound(s) Related to This m6A-centered Crosstalk
E3 ubiquitin-protein ligase Mdm2 (Mdm2) 17 Compound(s) Regulating the Target Click to Show/Hide the Full List
 Compound Name RG7388 Phase 3 [5]
Synonyms
Idasanutlin; 1229705-06-9; Idasanutlin (RG-7388); RG-7388; UNII-QSQ883V35U; QSQ883V35U; CHEMBL2402737; Benzoic acid, 4-((((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-2-pyrrolidinyl)carbonyl)amino)-3-methoxy-; RO5503781; Idasanutlin [USAN:INN]; Benzoic acid, 4-[[[(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-2-pyrrolidinyl]carbonyl]amino]-3-methoxy-; RG-7388;Idasanutlin; RO-5503781; SCHEMBL442856
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MOA Modulator
Activity IC50 = 6 nM
External Link
CID: 53358942
TTD: D0OC4O
DrugBank: DB12325
 Compound Name AMG 232 Phase 2 [6]
Synonyms
KRT-232
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MOA Modulator
Activity IC50 = 0.6 nM
External Link
CID: 58573469
TTD: D0C1WR
DrugBank: DB15299
 Compound Name APG-115 Phase 2 [7]
Synonyms
15Qau0SI9J; UNII-15QAU0SI9J; 1818393-16-6; APG 115 [WHO-DD]; SCHEMBL17189805; Bicyclo(2.2.2)octane-1-carboxylic acid, 4-((((3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-1'-ethyl-1'',2''-dihydro-2''-oxodispiro(cyclohexane-1,2'-pyrrolidine-3',3''-(3H)indol)-5'-yl)carbonyl)amino)-
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MOA Inhibitor
Activity Ki < 1 nM
External Link
CID: 91972012
TTD: D04SXL
 Compound Name ALRN-6924 Phase 2 [7]
MOA Antagonist
External Link
TTD: D07UKT
 Compound Name ASTX295 Phase 1/2 [8]
MOA Antagonist
External Link
TTD: DE7N6F
 Compound Name DS-3032 Phase 1 [9]
MOA Inhibitor
External Link
TTD: D08JSQ
 Compound Name RG7775 Phase 1 [10]
MOA Inhibitor
External Link
TTD: D08TNG
 Compound Name JNJ-26854165 Phase 1 [11]
Synonyms
Serdemetan; 881202-45-5; N1-(2-(1H-Indol-3-yl)ethyl)-N4-(pyridin-4-yl)benzene-1,4-diamine; JNJ-26854165 (Serdemetan); UNII-ID6YB4W3V8; ID6YB4W3V8; C21H20N4; n-(2-(1h-indol-3-yl)ethyl)-n'-(4-pyridinyl)-1,4-benzenediamine; N-[2-(1H-INDOL-3-YL)ETHYL]-N'-(4-PYRIDINYL)-1,4-BENZENEDIAMINE; Serdemetan [INN]; MLS006011022; SCHEMBL3012498; CHEMBL2137530; CTK8C1936; EX-A267; DTXSID30236830; MolPort-009-679-468; HMS3654A16; JNJ 26854165 (Serdemetan); BCP02124; AOB87702; QC-534; ANW-67474
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MOA Modulator
External Link
CID: 11609586
TTD: D0B3GF
DrugBank: DB12027
 Compound Name BI 907828 Phase 1 [12]
MOA Inhibitor
External Link
TTD: DW3AX4
 Compound Name HDM201 Phase 1 [7]
MOA Inhibitor
Activity Ki = 0.21 nM
External Link
CID: 71678098
TTD: D01KTG
 Compound Name MI-219 Investigative [13]
Synonyms
CHEMBL572933; (2'R,3S,4'R,5'R)-6-chloro-4'-(3-chlorophenyl)-N-((S)-3,4-dihydroxybutyl)-5-fluoro-2'-neopentyl-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide; 908027-55-4; SCHEMBL2624351; BDBM50300121; US8680132, MI- 219; (2''R,3S,4''R,5''R)-6-chloro-4''-(3-chlorophenyl)-N-((S)-3,4-dihydroxybutyl)-5-fluoro-2''-neopentyl-2-oxospiro[indoline-3,3''-pyrrolidine]-5''-carboxamide; (3S)-N-[(3S)-3,4-Dihydroxybutyl]-5-fluoro-6-chloro-2-oxo-2'alpha-(2,2-dimethylpropyl)-4'beta-(3-chlorophenyl)spiro[1H-indole-3(2H),3'-pyrrolidine]-5'alpha-carboxamide
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MOA Inhibitor
External Link
CID: 24877503
TTD: DNY16U
 Compound Name ISIS 16518 Investigative [14]
External Link
TTD: D02JFF
 Compound Name PLSQETFSDLWKLLPEN-NH2 Investigative [14]
Synonyms
CHEMBL267823
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Activity Ki = 6670 nM
External Link
CID: 44412124
TTD: D08YAF
 Compound Name NSC-66811 Investigative [14]
Synonyms
NSC 66811; 6964-62-1; 2-METHYL-7-[PHENYL(PHENYLAMINO)METHYL]-8-QUINOLINOL; 7-[anilino(phenyl)methyl]-2-methylquinolin-8-ol; 7-(Anilino(phenyl)-methyl)-2-methyl-8-quinolinol; 2-methyl-7-(phenyl(phenylamino)methyl)quinolin-8-ol; 8-Hydroxy-2-methyl-7-[phenyl(phenylamino)methyl]quinoline; NSC66811; AC1L6NIN; AC1Q79MP; 7-(anilino(phenyl)methyl)-2-methyl-8-quinolinol; SCHEMBL1241576; CHEMBL210778; BDBM31206; CTK5D0724; DTXSID30290119; MolPort-008-431-978; BCP07490; 2152AH; AKOS003020553; AKOS016050521; AK260645; M2390
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Activity Ki = 120 nM
External Link
CID: 248986
TTD: D0C0TN
 Compound Name ISIS 16507 Investigative [14]
External Link
TTD: D0Y3JR
 Compound Name NUTLIN-3 Investigative [14]
Synonyms
548472-68-0; 890090-75-2; nutlin-3A; nutlin 3; (+/-)-Nutlin3; CHEMBL211045; Nutlin 3(Random Configuration); MDM2 Antagonist, Nutlin-3, Racemic; 4-(4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole-1-carbonyl)piperazin-2-one; 4-({4,5-bis(4-chlorophenyl)-2-[4-methoxy-2-(propan-2-yloxy)phenyl]-4,5-dihydro-1H-imidazol-1-yl}carbonyl)piperazin-2-one; 4-[4,5-bis(4-chlorophenyl)-2-(4-methoxy-2-propan-2-yloxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazin-2-one
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Activity Ki = 30 nM
External Link
CID: 216345
TTD: D01QKK
 Compound Name NU-8231 Investigative [14]
Synonyms
SCHEMBL2454464; CHEMBL360944
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External Link
CID: 11648438
TTD: D0F1SN
References
Ref 1 N?-Methyladenosine Landscape of Glioma Stem-Like Cells: METTL3 Is Essential for the Expression of Actively Transcribed Genes and Sustenance of the Oncogenic Signaling. Genes (Basel). 2019 Feb 13;10(2):141. doi: 10.3390/genes10020141.
Ref 2 ADAR1 is a new target of METTL3 and plays a pro-oncogenic role in glioblastoma by an editing-independent mechanism. Genome Biol. 2021 Jan 28;22(1):51. doi: 10.1186/s13059-021-02271-9.
Ref 3 ADAR1-mediated 3' UTR editing and expression control of antiapoptosis genes fine-tunes cellular apoptosis response. Cell Death Dis. 2017 May 25;8(5):e2833. doi: 10.1038/cddis.2017.12.
Ref 4 Hyper-Editing of Cell-Cycle Regulatory and Tumor Suppressor RNA Promotes Malignant Progenitor Propagation. Cancer Cell. 2019 Jan 14;35(1):81-94.e7. doi: 10.1016/j.ccell.2018.11.017. Epub 2019 Jan 3.
Ref 5 Pre-clinical evaluation of the MDM2-p53 antagonist RG7388 alone and in combination with chemotherapy in neuroblastoma. Oncotarget. 2015 Apr 30;6(12):10207-21. doi: 10.18632/oncotarget.3504.
Ref 6 Discovery of a small molecule MDM2 inhibitor (AMG 232) for treating cancer. J Med Chem. 2014 Aug 14;57(15):6332-41. doi: 10.1021/jm500627s. Epub 2014 Jul 9.
Ref 7 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
Ref 8 Clinical pipeline report, company report or official report of Astex Pharmaceuticals.
Ref 9 Drugging the p53 pathway: understanding the route to clinical efficacy. Nat Rev Drug Discov. 2014 Mar;13(3):217-36. doi: 10.1038/nrd4236.
Ref 10 Phase I clinical trail of RG7775 for treating Acute myelogenous leukemia. Roche.
Ref 11 Serdemetan antagonizes the Mdm2-HIF1Alpha axis leading to decreased levels of glycolytic enzymes. PLoS One. 2013 Sep 6;8(9):e74741. doi: 10.1371/journal.pone.0074741. eCollection 2013.
Ref 12 MDM2 inhibition: an important step forward in cancer therapy. Leukemia. 2020 Nov;34(11):2858-2874. doi: 10.1038/s41375-020-0949-z. Epub 2020 Jul 10.
Ref 13 MI-219-zinc combination: a new paradigm in MDM2 inhibitor-based therapy. Oncogene. 2011 Jan 6;30(1):117-26. doi: 10.1038/onc.2010.403. Epub 2010 Sep 6.
Ref 14 TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751.