m6A-centered Crosstalk Information

Mechanism of Crosstalk between m6A Modification and Epigenetic Regulation
Crosstalk ID
M6ACROT00123
 [1], [2], [3]
m6A modification ADAR1 ADAR1 METTL3 Methylation : m6A sites Direct Enhancement RNA modification DHFR DHFR 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 Dihydrofolate reductase (DHFR) 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 Dihydrofolate reductase (DHFR) transcript.
Responsed Drug Trimethoprim
 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
MCF-7 Invasive breast carcinoma Homo sapiens CVCL_0031
Full List of Potential Compound(s) Related to This m6A-centered Crosstalk
Dihydrofolate reductase (DHFR) 12 Compound(s) Regulating the Target Click to Show/Hide the Full List
 Compound Name Trimethoprim Approved [4]
Synonyms
Abaprim; Alprim; Anitrim; Antrima; Antrimox; Bacdan; Bacidal; Bacide; Bacin; Bacta; Bacterial; Bacticel; Bactin; Bactoprim; Bactramin; Bencole; Bethaprim; Biosulten; Briscotrim; Chemotrin; Cidal; Colizole; Conprim; Cotrimel; Deprim; Duocide; Esbesul; Espectrin; Euctrim; Exbesul; Fermagex; Fortrim; Futin; Idotrim; Ikaprim; Instalac; Kombinax; Lagatrim; Lastrim; Methoprim; Metoprim; Monoprim; Monotrim; Monotrimin; Novotrimel; Omstat; Oraprim; Pancidim; Polytrim; Priloprim; Primosept; Primsol; Proloprim; Protrin; Purbal; Resprim; Roubac; Roubal; Salvatrim; Setprin; Sinotrim; Stopan; Streptoplus; Sugaprim; Sulfamar; Sulfamethoprim; Sulfoxaprim; Sulmeprim; Sulthrim; Sultrex; Syraprim; Tiempe; Toprim; Trimanyl; Trimethioprim; Trimethoprime; Trimethoprimum; Trimethopriom; Trimetoprim; Trimetoprima; Trimexazole; Trimexol; Trimezol; Trimogal; Trimono; Trimopan; Trimpex; Triprim; Trisul; Trisulcom; Trisulfam; Trisural; Uretrim; Urobactrim; Utetrin; Velaten; Wellcoprim; Wellcoprin; Xeroprim; Zamboprim; Bacterial [Antibiotic]; Colizole DS; Component of Bactrim; Component of Septra; Lagatrim Forte; ResprimForte; Septrin DS; Septrin Forte; Septrin S; Trimetoprim [DCIT]; Trimetoprim [Polish]; BW 5672; KUC103659N; NIH 204; T 7883; Trimpex 200; WR 5949; Alcorim-F; Apo-Sulfatrim; BW 56-72; Co-Trimoxizole; Monotrim (TN); NIH 204 (VAN); Proloprim (TN); Smz-Tmp; Sulfamethoxazole & Trimethoprim; TCMDC-125538; Tmp-Ratiopharm; Trimeth/Sulfa; Trimethopim(TMP); Trimethoprim & VRC3375; Trimethoprime [INN-French]; Trimethoprimum [INN-Latin]; Trimetoprima [INN-Spanish]; Trimez-IFSA; Trimpex (TN); Triprim (TN); U-Prin; Uro-D S; BW-56-72; KSC-4-158; AZT + TMP/SMX (mixture) combination; Trimethoprim (JAN/USP/INN); Trimethoprim [USAN:BAN:INN:JAN]
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MOA Modulator
Activity Ki = 0.006 nM
External Link
CID: 5578
TTD: D0AO5H
DrugBank: DB00440
 Compound Name Leucovorin Calcium Approved [5]
Synonyms
Leucovorin Calcium Preservative Free; Wellcovorin
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MOA Modulator
External Link
CID: 135403647
TTD: D0B6TW
 Compound Name Methotrexate Sodium Approved [4]
Synonyms
Methotrexate disodium salt; 7413-34-5; Sodium methotrexate; MTX disodium; methotrexate disodium; UNII-3IG1E710ZN; 3IG1E710ZN; CHEBI:50679; Amethopterin sodium; Disodium methotrexate; Methotrexat dinatrium; Mexate-Aq Preserved; Methotrexate sodium salt; EINECS 231-022-0; 59-05-2 (Parent); Methotrexate Preservative Free; 4-Amino-N(sup 10)-methylpteroylglutamic acid disodium salt; METHOTREXATE SODIUM PRESERVATIVE FREE
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MOA Modulator
External Link
CID: 11329481
TTD: D0D3DU
 Compound Name Aminosalicylic Acid Approved [4]
Synonyms
4-Aminosalicylic acid; 65-49-6; P-AMINOSALICYLIC ACID; Rezipas; Aminopar; Pamisyl; Parasalindon; Ferrosan; Deapasil; Apacil; Parasal; Paser; Paramycin; Gabbropas; Parasalicil; Pasnodia; Osacyl; Aminox; Pasolac; Pasmed; Propasa; Pasalon; Entepas; Pasdium; Pasara; Pamacyl; Pasem; Pasa; 2-Hydroxy-4-aminobenzoic acid; PASK; APAS; Para-Pas; Sanipirol-4; Hellipidyl; Pascorbic; PAS-C; Benzoic acid, 4-amino-2-hydroxy-; PAS (acid); Aminosalicylic Acid Resin Complex; Aminosalicylate Sodium
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MOA Modulator
External Link
CID: 4649
TTD: D01WJL
DrugBank: DB00233
 Compound Name Iclaprim Application submitted [6]
Synonyms
192314-93-5; AR-100; 5-[(2-cyclopropyl-7,8-dimethoxy-2h-chromen-5-yl)methyl]pyrimidine-2,4-diamine; RO-48-2622; Mersarex; 5-((2-Cyclopropyl-7,8-dimethoxy-2H-chromen-5-yl)methyl)pyrimidine-2,4-diamine; Iclaprim [USAN:INN]; Iclaprim (USAN/INN); 2,4-Pyrimidinediamine, 5-((2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl)methyl)-; 2,4-Pyrimidinediamine, 5-[(2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl)methyl]-; AR 100; AC1Q4WM5; SCHEMBL379386; CHEMBL134561; AC1L4U54; SCHEMBL12899446; CTK4E0971; BDBM18070; Iclaprim [INN]; AR-102; AR-100001; 5-((2RS)-2-cyclopropyl-7,8-dimethoxy-2H-chromen-5-ylmethyl)pyrimidine-2,4-diamine
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MOA Inhibitor
Activity IC50 = 8 nM
External Link
CID: 213043
TTD: D04LBC
DrugBank: DB06358
 Compound Name CH-4051 Phase 2 [7]
MOA Inhibitor
External Link
CID: 11532464
TTD: D02OTK
 Compound Name PIRITREXIM Phase 2 [8]
Synonyms
72732-56-0; Piritrexim [INN]; Piritreximum [Latin]; Piritrexime [French]; 6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine; Piritrexima [Spanish]; BW 301U; UNII-MK2A783ZUT; BW-301U; TCMDC-137235; BRN 5768301; MK2A783ZUT; CHEMBL7492; 2,4-Diamino-5-methyl-6-(2,5-dimethoxybenzyl)pyrido(2,3-d)pyrimidine; 6-(2,5-DIMETHOXY-BENZYL)-5-METHYL-PYRIDO[2,3-D]PYRIMIDINE-2,4-DIAMINE; 6-((2,5-Dimethoxyphenyl)methyl)-5-methylpyrido(2,3-d)pyrimidine-2,4-diamine
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MOA Modulator
Activity Ki = 0.025 nM
External Link
CID: 54369
TTD: D09AYQ
DrugBank: DB03695
 Compound Name MDAM (y-methylene-10-deazaaminopterin) Phase 1 [9]
MOA Inhibitor
External Link
TTD: D0DO5J
 Compound Name L-MDAM Phase 1 [10]
Synonyms
176857-41-3; UNII-W9CXL7O6LL; W9CXL7O6LL; GAMMA-METHYLENE-10-DEAZAAMINOPTERIN; MDAM; SCHEMBL1065136; ZINC1542008; KB-78169; Z-3290; L-Glutamic acid, N-(4-(2-(2,4-diamino-6-pteridinyl)ethyl)benzoyl)-4-methylene-; (2S)-2-[4-[2-(2,4-Diamino-6-pteridinyl)ethyl]benzoylamino]-4-methyleneglutaric acid
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MOA Inhibitor
External Link
CID: 9803852
TTD: D0S9OH
 Compound Name VYR 006 Phase 1 [11]
MOA Inhibitor
External Link
TTD: D9ZQ7T
 Compound Name TNP-351 Discontinued in Phase 2 [12]
Synonyms
N-[4-[3-(2,4-Diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]benzoyl]-L-glutamic acid
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MOA Inhibitor
External Link
CID: 5487322
TTD: D00CQW
 Compound Name 1954U89 Preclinical [13]
MOA Modulator
Activity Ki = 0.0003 nM
External Link
CID: 177894
TTD: D05HCO
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 A-to-I RNA Editing Up-regulates Human Dihydrofolate Reductase in Breast Cancer. J Biol Chem. 2017 Mar 24;292(12):4873-4884. doi: 10.1074/jbc.M117.775684. Epub 2017 Feb 10.
Ref 4 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
Ref 5 Biochemical factors in the selectivity of leucovorin rescue: selective inhibition of leucovorin reactivation of dihydrofolate reductase and leucovorin utilization in purine and pyrimidine biosynthesis by methotrexate and dihydrofolate polyglutamates.NCI Monogr.1987;(5):17-26.
Ref 6 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
Ref 7 CH-1504, a metabolically inert antifolate for the potential treatment of rheumatoid arthritis. IDrugs. 2010 Aug;13(8):559-67.
Ref 8 Structural variations of piritrexim, a lipophilic inhibitor of human dihydrofolate reductase: synthesis, antitumor activity and molecular modeling ... Eur J Med Chem. 2004 Dec;39(12):1079-88.
Ref 9 Evaluation of the importance of hydrophobic interactions in drug binding to dihydrofolate reductase. J Med Chem. 1988 Jan;31(1):129-37.
Ref 10 Polyglutamylation of the dihydrofolate reductase inhibitor gamma-methylene-10-deazaaminopterin is not essential for antitumor activity. Clin Cancer Res. 1996 Apr;2(4):707-12.
Ref 11 Clinical pipeline report, company report or official report of Vyera Pharmaceuticals.
Ref 12 A Ring-Transformation/Ring-Annulation Strategy for the Synthesis of the DHFR Inhibitor, TNP-351: A Correction. J Org Chem. 1996 Nov 1;61(22):7973-7974.
Ref 13 The pharmacokinetics of 1954U89, 1,3-diamino-7-(1-ethylpropyl)-8-methyl-7H-pyrrolo-(3,2-f)quinazoline, in dogs and rats after intravenous and oral administration. Biopharm Drug Dispos. 1997 Jul;18(5):433-42.