m6A-centered Crosstalk Information

Mechanism of Crosstalk between m6A Modification and Epigenetic Regulation
Crosstalk ID
M6ACROT00649
 [1], [2], [3], [4], [5], [6], [7]
m6A modification MIR221 MIR221 METTL3 Methylation : m6A sites Indirect Enhancement RNA modification SIRT1 SIRT1 FTO Demethylation : modification sites
m6A Modification:
m6A Regulator Methyltransferase-like 3 (METTL3) WRITER
 Regulator Info 
m6A Target microRNA 221 (MIR221)
 Targert Gene 
Epigenetic Regulation that have Cross-talk with This m6A Modification:
Epigenetic Regulation Type RNA modification (RNAMod)  >> N6,2'-O-dimethyladenosine (m6Am)
Epigenetic Regulator Fat mass and obesity-associated protein (FTO) ERASER View Details
Regulated Target NAD-dependent protein deacetylase sirtuin-1 (SIRT1) View Details
Crosstalk Relationship m6A  →  m6Am Enhancement
Crosstalk Mechanism m6A modification indirectly impacts RNA modification through downstream signaling pathways
Crosstalk Summary METTL3 interacts with microRNA 221 (MIR221), decreasing its m6A level and promoting its physical interaction with NAD-dependent protein deacetylase sirtuin-1 (SIRT1), which was regulated by FTO-mediated m6Am modification.
In-vitro Model
 Hep-G2 Hepatoblastoma Homo sapiens CVCL_0027
Hep 3B2.1-7 Childhood hepatocellular carcinoma Homo sapiens CVCL_0326
T24 Bladder carcinoma Homo sapiens CVCL_0554
Ej138 Bladder carcinoma Homo sapiens CVCL_2443
MCF-7 Invasive breast carcinoma Homo sapiens CVCL_0031
Full List of Potential Compound(s) Related to This m6A-centered Crosstalk
NAD-dependent protein deacetylase sirtuin-1 (SIRT1) 22 Compound(s) Regulating the Target Click to Show/Hide the Full List
 Compound Name Resveratrol Phase 3 [8]
Synonyms
Resvida; KUC104385N; R 5010; SRT 501; Cis-resveratrol; PREVENTION 8 (RESVERATROL); RM-1812; SRT-501; Trans-resveratrol; CU-01000001503-3; KSC-10-164; Resveratrol-3-sulfate; Trans-3,4',5-trihydroxystilbene; Trans-3,4′,5-Trihydroxystilbene; Trans-1,2-(3,4',5-Trihydroxydiphenyl)ethylene; (E)-5-(2-(4-hydroxyphenyl)ethenyl)-1,3-benzenediol
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MOA Inhibitor
Activity EC50 = 23600 nM
External Link
CID: 445154
TTD: D0U3EP
DrugBank: DB02709
 Compound Name GSK2245840 Phase 2 [9]
Synonyms
Gepirone hydrochloride; Gepirone HCl; UNII-80C9L8EP6V; Gepirone hydrochloride [USAN]; 80C9L8EP6V; 83928-66-9; CHEMBL1204187; Gepirone hydrochloride (USAN); BMY 138951; AC1Q3ELB; AC1L1IK3; SCHEMBL318838; DTXSID30232812; AOB5299; 83928-76-1 (Parent); ORG-33062; SB19633; BMY-13805-1; BMY 13805-1; 3,3-Dimethyl-1-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)glutarimide monohydrochloride; D04314; 4,4-dimethyl-1-[4-(4-pyrimidin-2-ylpiperazin-1-yl)butyl]piperidine-2,6-dione hydrochloride; 2,6-Piperidinedione,
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MOA Modulator
External Link
CID: 25108829
TTD: D04JNI
DrugBank: DB12186
 Compound Name SEN-196 Phase 2 [10]
Synonyms
EX-527; SEN-0014196; SIRT1 inhibitors (Huntingtons disease), Elixir/Siena; Sirtuin-1 inhibitors (oral, Huntington's disease), Elixir/Siena
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MOA Inhibitor
Activity IC50 = 85 nM
External Link
CID: 5113032
TTD: D0E3LP
DrugBank: DB13978
 Compound Name MB-12066 Phase 2 [11]
Synonyms
B-lapachone (obesity), Mazence; Beta-lapachone (obesity), Mazence
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MOA Modulator
External Link
TTD: D0TU7V
 Compound Name SRT2379 Phase 1 [12]
MOA Modulator
External Link
TTD: D0O3EP
 Compound Name SRT3025 Phase 1 [13]
MOA Modulator
External Link
CID: 46245047
TTD: D0X3TI
 Compound Name PMID25435179-Compound-WO2012106509Salermide Patented [8]
MOA Inhibitor
External Link
TTD: D02QKC
 Compound Name CAMBINOL Patented [14]
Synonyms
14513-15-6; SIRT1/2 Inhibitor IV, Cambinol; NSC112546; NSC-112546; NSC-1125476; 5-[(2-hydroxy-1-naphthyl)methyl]-2-mercapto-6-phenyl-4(3H)-Pyrimidinone; 5-(2-Hydroxynaphthalen-1-ylmethyl)-6-phenyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one; 5-(2-Hydroxy-naphthalen-1-ylmethyl)-6-phenyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one; Tetrahydro-5-[(2-hydroxy-1-naphthalenyl)methyl]-6-phenyl-2-thioxo-4(1H)-Pyrimidinone; AC1MMYEF; NCIStruc2_001159; NCIStruc1_001428; SCHEMBL2538372; CHEMBL491960; CTK8G3107; BDBM29040
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MOA Inhibitor
Activity IC50 = 8850 nM
External Link
CID: 3246390
TTD: D04JZE
DrugBank: DB15493
 Compound Name PMID25435179-Compound-WO2012106509CAY10602 Patented [8]
MOA Inhibitor
External Link
TTD: D06IHB
 Compound Name PMID25435179-Compound-WO2012106509Tenovin-6 Patented [8]
MOA Inhibitor
External Link
TTD: D0PE8E
 Compound Name GSK184072 Discontinued in Phase 2 [15]
Synonyms
Flutimide; 162666-34-4; AC1O5YLM; AKOS027326745; (5Z)-1-hydroxy-3-isobutyl-5-(2-methylpropylidene)pyrazine-2,6-dione; 2,6-(1H,3H)-Pyrazinedione, 1-hydroxy-5-(2-methylpropyl)-3-(2-methylpropylidene)-, (Z)-; 2,6-(1H,3H)-Pyrazinedione, 1-hydroxy-5-(2-methylpropyl)-3-(2-methylpropylidene)-, (3Z)-; (5Z)-1-hydroxy-3-(2-methylpropyl)-5-(2-methylpropylidene)pyrazine-2,6-dione
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MOA Activator
External Link
CID: 6443207
TTD: D0R3EL
 Compound Name Meta-sirtinol Investigative [16]
MOA Inhibitor
Activity IC50 = 59000 nM
External Link
CID: 135461039
TTD: D00LYI
 Compound Name 2H-chromeno[2,3-d]pyrimidine-2,4(3H)-dione Investigative [17]
Synonyms
CHEMBL611665; chromeno[2,3-d]pyrimidine-2,4-dione; AC1LQMEG; 5-Deaza-10-oxaflavin; SCHEMBL11333239; BFMCRAXOACCPEL-UHFFFAOYSA-; ZINC1280587; STK236511; BDBM50309832; AKOS000428551; MCULE-3496773034; ST50987740; 3-hydrochromeno[2,3-d]pyrimidine-2,4-dione; 2H,3H,4H-chromeno[2,3-d]pyrimidine-2,4-dione; 2H-[1]Benzopyrano[2,3-d]pyrimidine-2,4(3H)-dione; InChI=1/C11H6N2O3/c14-9-7-5-6-3-1-2-4-8(6)16-10(7)13-11(15)12-9/h1-5H,(H,12,14,15)
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MOA Inhibitor
Activity IC50 = 5300 nM
External Link
CID: 1403654
TTD: D02AYX
 Compound Name (R)-sirtinol Investigative [16]
MOA Inhibitor
Activity IC50 = 55000 nM
External Link
CID: 1376646
TTD: D02EWM
 Compound Name SRT1720 Investigative [18]
Synonyms
925434-55-5; N-(2-(3-(piperazin-1-ylmethyl)imidazo[2,1-b]thiazol-6-yl)phenyl)quinoxaline-2-carboxamide; SRT 1720; SRT-1720; CHEMBL257991; N-[2-[3-(1-PIPERAZINYLMETHYL)IMIDAZO[2,1-B]THIAZOL-6-YL]PHENYL]-2-QUINOXALINECARBOXAMIDE; N-(2-{3-[(Piperazin-1-yl)methyl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)quinoxaline-2-carboxamide; Tafluprost enone; N-[2-[3-(piperazin-1-ylmethyl)imidazo[2,1-b]thiazol-6-yl]phenyl]quinoxaline-2-carboxamide; IASPBORHOMBZMY-UHFFFAOYSA-N
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MOA Activator
External Link
CID: 25232708
TTD: D03EGA
 Compound Name YK-3237 Investigative [19]
Synonyms
Angiogenesis inhibitors (cancer); Angiogenesis inhibitors (cancer), Georgetown University
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MOA Inhibitor
External Link
TTD: D05UDU
 Compound Name splitomicin Investigative [17]
Synonyms
1,2-Dihydro-3H-naphtho[2,1-b]pyran-3-one; 1,2-dihydro-3h-benzo[f]chromen-3-one; 1H-benzo[f]chromen-3(2H)-one; CHEMBL86537; CHEBI:75272; 1,2-dihydrobenzo[f]chromen-3-one; 1H,2H,3H-naphtho[2,1-b]pyran-3-one; Splitomycin; Bio2_000878; Tocris-1542; AC1L1JZ6; AC1Q6ML4; KBioGR_000456; BSPBio_001116; KBioSS_000456; GTPL8101; SCHEMBL2544804; ZINC27374; KBio3_000852; KBio2_003024; BDBM29590; KBio3_000851; KBio2_005592; KBio2_000456; MolPort-003-959-546; ISFPDBUKMJDAJH-UHFFFAOYSA-N; HMS1362H17; HMS1990H17; Bio2_000398
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MOA Inhibitor
Activity IC50 = 96200 nM
External Link
CID: 5269
TTD: D09SUO
 Compound Name 2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide Investigative [20]
Synonyms
CHEMBL112265; 352549-39-4; CBMicro_001045; Cambridge id 5870454; AC1N6ME3; Oprea1_743470; SCHEMBL251128; CTK1B0687; DTXSID20401358; MolPort-000-735-346; HMS1632P07; SMSF0008851; STL525366; BDBM50178767; carboxamido-1,2,3-tetrahydrocarbazole; AKOS004917884; CB02357; BIM-0000968.P001; SR-01000154363; SR-01000154363-1; 1H-Carbazole-1-carboxamide, 2,3,4,9-tetrahydro-
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MOA Inhibitor
Activity IC50 = 1470 nM
External Link
CID: 4262314
TTD: D0E1QP
 Compound Name (S)-sirtinol Investigative [16]
MOA Inhibitor
Activity IC50 = 67000 nM
External Link
CID: 1376645
TTD: D0F1KR
 Compound Name Para-sirtinol Investigative [16]
MOA Inhibitor
Activity IC50 = 13000 nM
External Link
CID: 135491748
TTD: D0UO1E
 Compound Name Ro31-8220 Investigative [21]
Synonyms
Bisindolylmaleimide IX; ro 31-8220; 125314-64-9; Ro 31 8220; Ro 318220; UNII-W9A0B5E78O; Ro-318220; Ro-31-8220; CHEMBL6291; W9A0B5E78O; CHEBI:38912; 3-{3-[4-(1-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-1H-indol-1-yl}propyl carbamimidothioate; 3-{3-[4-(1-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-1H-indol-1-yl}propyl imidothiocarbamate; CHEMBL1591531; Carbamimidothioic acid, 3-(3-(2,5-dihydro-4-(1-methyl-1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl)-1H-indol-1-yl)propyl; bisindolymaleimide IX
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MOA Inhibitor
Activity IC50 = 3500 nM
External Link
CID: 5083
TTD: D0M5FF
 Compound Name RO-316233 Investigative [21]
Synonyms
119139-23-0; bisindolylmaleimide iv; 3,4-di(1H-indol-3-yl)-1H-pyrrole-2,5-dione; Arcyriarubin A; 3,4-Bis(3-indolyl)maleimide; 3,4-Di-1H-indol-3-yl-1H-pyrrole-2,5-dione; UNII-MBK3OO5K8T; BIM IV; 3,4-bis(1H-indol-3-yl)pyrrole-2,5-dione; MBK3OO5K8T; CHEMBL266487; 3,4-bis(1H-indol-3-yl)-2,5-dihydro-1H-pyrrole-2,5-dione; DQYBRTASHMYDJG-UHFFFAOYSA-N; 2,3-bis(1H-Indol-3-yl)maleimide; 1H-Pyrrole-2,5-dione, 3,4-di-1H-indol-3-yl-; Ro-31-6233; AK-15401; 3,4-bis(3-indolyl)-1H-pyrrole-2,5-dione; Bisindoylmaleimide; Bisindolyl deriv. 3
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MOA Inhibitor
External Link
CID: 2399
TTD: D0L8HO
References
Ref 1 SIRT1 Regulates N(6) -Methyladenosine RNA Modification in Hepatocarcinogenesis by Inducing RANBP2-Dependent FTO SUMOylation. Hepatology. 2020 Dec;72(6):2029-2050. doi: 10.1002/hep.31222. Epub 2020 Oct 22.
Ref 2 METTL3 promote tumor proliferation of bladder cancer by accelerating pri-miR221/222 maturation in m6A-dependent manner. Mol Cancer. 2019 Jun 22;18(1):110. doi: 10.1186/s12943-019-1036-9.
Ref 3 METTL3 promotes adriamycin resistance in MCF-7 breast cancer cells by accelerating pri-microRNA-221-3p maturation in a m6A-dependent manner. Exp Mol Med. 2021 Jan;53(1):91-102. doi: 10.1038/s12276-020-00510-w. Epub 2021 Jan 8.
Ref 4 MiR-221/SIRT1/Nrf2 signal axis regulates high glucose induced apoptosis in human retinal microvascular endothelial cells. BMC Ophthalmol. 2020 Jul 22;20(1):300. doi: 10.1186/s12886-020-01559-x.
Ref 5 Long noncoding RNA GAS5 inhibits cell proliferation and fibrosis in diabetic nephropathy by sponging miR-221 and modulating SIRT1 expression. Aging (Albany NY). 2019 Oct 20;11(20):8745-8759. doi: 10.18632/aging.102249. Epub 2019 Oct 20.
Ref 6 LincRNA-p21 alleviates atherosclerosis progression through regulating the miR-221/SIRT1/Pcsk9 axis. J Cell Mol Med. 2021 Oct;25(19):9141-9153. doi: 10.1111/jcmm.16771. Epub 2021 Sep 19.
Ref 7 miR-221 promotes lens epithelial cells apoptosis through interacting with SIRT1 and E2F3. Chem Biol Interact. 2019 Jun 1;306:39-46. doi: 10.1016/j.cbi.2019.03.021. Epub 2019 Mar 26.
Ref 8 Sirtuin modulators: an updated patent review (2012 - 2014).Expert Opin Ther Pat. 2015 Jan;25(1):5-15.
Ref 9 Sirtuin 1 activator SRT2104 protects Huntington's disease mice. Ann Clin Transl Neurol. 2014 Dec;1(12):1047-52. doi: 10.1002/acn3.135. Epub 2014 Oct 31.
Ref 10 Sirtuin 1 (SIRT1): the misunderstood HDAC. J Biomol Screen. 2011 Dec;16(10):1153-69. doi: 10.1177/1087057111422103. Epub 2011 Nov 15.
Ref 11 Pharmacological activation of Sirt1 ameliorates polyglutamine-induced toxicity through the regulation of autophagy. PLoS One. 2013 Jun 10;8(6):e64953. doi: 10.1371/journal.pone.0064953. Print 2013.
Ref 12 SRT2379, a small-molecule SIRT1 activator, fails to reduce cytokine release in a human endotoxemia model. Critical Care 2013, 17(Suppl 4):P8.
Ref 13 The Sirt1 Activators SRT2183 and SRT3025 Inhibit RANKL-Induced Osteoclastogenesis in Bone Marrow-Derived Macrophages and Down-Regulate Sirt3 in Sirt1 Null Cells. PLoS One. 2015 Jul 30;10(7):e0134391. doi: 10.1371/journal.pone.0134391. eCollection 2015.
Ref 14 Novel cambinol analogs as sirtuin inhibitors: synthesis, biological evaluation, and rationalization of activity. J Med Chem. 2009 May 14;52(9):2673-82. doi: 10.1021/jm8014298.
Ref 15 Clinical pipeline report, company report or official report of GlaxoSmithKline (2009).
Ref 16 Design, synthesis, and biological evaluation of sirtinol analogues as class III histone/protein deacetylase (Sirtuin) inhibitors. J Med Chem. 2005 Dec 1;48(24):7789-95. doi: 10.1021/jm050100l.
Ref 17 Characterization of sirtuin inhibitors in nematodes expressing a muscular dystrophy protein reveals muscle cell and behavioral protection by specific sirtinol analogues. J Med Chem. 2010 Feb 11;53(3):1407-11. doi: 10.1021/jm9013345.
Ref 18 Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature. 2007 Nov 29;450(7170):712-6. doi: 10.1038/nature06261.
Ref 19 URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2707).
Ref 20 Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1. J Med Chem. 2005 Dec 15;48(25):8045-54. doi: 10.1021/jm050522v.
Ref 21 Adenosine mimetics as inhibitors of NAD+-dependent histone deacetylases, from kinase to sirtuin inhibition. J Med Chem. 2006 Dec 14;49(25):7307-16. doi: 10.1021/jm060118b.