m6A-centered Crosstalk Information

Mechanism of Crosstalk between m6A Modification and Epigenetic Regulation
Crosstalk ID
M6ACROT03503
 [1], [2]
Histone modification H3K4me3 KMT2A METTL3 Direct Enhancement m6A modification TLR2 TLR2 METTL3 Methylation : m6A sites
m6A Modification:
m6A Regulator Methyltransferase-like 3 (METTL3) WRITER
 Regulator Info 
m6A Target Toll-like receptor 2 (TLR2)
 Targert Gene 
Epigenetic Regulation that have Cross-talk with This m6A Modification:
Epigenetic Regulation Type Histone modification (HistMod)
Epigenetic Regulator Histone-lysine N-methyltransferase 2A (KMT2A) WRITER View Details
Regulated Target Histone H3 lysine 4 trimethylation (H3K4me3) View Details
Downstream Gene METTL3 View Details
Crosstalk Relationship Histone modification  →  m6A Enhancement
Crosstalk Mechanism histone modification directly impacts m6A modification through modulating the level of m6A regulator
Crosstalk Summary KMT2A-mediated Histone H3 lysine 4 trimethylation (H3K4me3) regulates the autophagy-GATA4 axis through METTL3-mediated m6A modification of ATG4a to promote NPCs senescence and IVDD progression. METTL3 stabilized Toll-like receptor 2 (TLR2) mRNA in an IGF2BP1-dependent manner. METTL3 silencing restored specific gut microbiota levels in IDD rats, which was further reversed by administration of Pam3CSK4. These results demonstrate the beneficial effects of METTL3 silencing on NPC senescence and amelioration of IVD injury, involving modulation of TLR2 m6A modification and gut microbiota. These findings support METTL3 silencing as a potential therapeutic target for IDD.
Responsed Disease Intervertebral disc degeneration ICD-11: FA80
 Disease Info 
In-vivo Model rats were anesthetized with 40 mg/kg sodium pentobarbital. A 21G needle was used to puncture discs 7-8 (Co7-8) from the back through the skin of the tail. The length of the needle was predetermined to ensure a puncture depth of approximately 5 mm. After penetrating the annulus, the needle was rotated 360° and held for 30 seconds to injure the annulus. The sham group underwent the same procedure but without puncture injury to the caudal disc.
Full List of Potential Compound(s) Related to This m6A-centered Crosstalk
Toll-like receptor 2 (TLR2) 9 Compound(s) Regulating the Target Click to Show/Hide the Full List
 Compound Name Cadi-05 Phase 3 [3]
Synonyms
Mycobacterium w; Poly-TLR agonist polyantigenic vaccine (cancer), Cadila; Poly-toll-like receptor agonist polyantigenic vaccine (cancer), Cadila
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External Link
TTD: D0V0JR
 Compound Name MCS-18 Phase 2 [4]
Synonyms
Helleborus purpurascens-derived anti-inflammatory analgesic (injection, autoimmune disease), DoNatur
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MOA Modulator
External Link
TTD: D03ONZ
 Compound Name OPN-305 Phase 2 [5]
Synonyms
OPN-301; TLR-specific mAbs (inflammatory diseases), Opsona; Toll-like receptor specific monoclonal antibodies (inflammatory diseases), Opsona
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External Link
TTD: D0VI9P
 Compound Name Lipoteichoic acid Phase 1/2 [6]
Synonyms
Oncomycin; Lipoteichoic acid (cancer); Lipoteichoic acid (cancer), Lunamed; TLR-2 modulator (subcutaneous, solid tumor), LUNAMeD; Toll like receptor-2 modulator (subcutaneous, solid tumor), LUNAMeD
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MOA Modulator
External Link
CID: 137349712
TTD: D00UVU
 Compound Name MALP-2S Phase 1/2 [7]
MOA Modulator
External Link
TTD: D0K3SM
 Compound Name OM-174 Phase 1 [8]
Synonyms
UNII-HC3530GGGG; HC3530GGGG; Defoslimod [INN]; OM 174 lipid; 2-Deoxy-6-o-(2-deoxy-2-((R)-3-hydroxytetradecanamido)-beta-D-glucopyranosyl)-2-((R)-3-hydroxytetradecanamido)-alpha-D-glucopyranose 1,6'-bis(dihydrogen phosphate) 2'(3)-laurate.; 2-Deoxy-6-O-(2-deoxy-2-((R)-3-hydroxytetradecanamido)-beta-D-glucopyranosyl)-2-((R)-3-hydroxytetradecanamido)-alpha-D-glucopyranose 1,6'-bis(dihydrogen phosphate) 2'(3)-laurate
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MOA Modulator
External Link
CID: 9833422
TTD: D09POQ
 Compound Name F-50040 Discontinued in Phase 1 [9]
Synonyms
Metastatic melanoma vaccine, Pierre Fabre; P40-ELA; Metastatic melanoma vaccine, BioMerieux-Pierre Fabre; Vaccine (melanoma), Pierre Fabre; Vaccine (melanoma), BioMerieux-Pierre Fabre
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MOA Modulator
External Link
TTD: D07CQJ
 Compound Name CBLB-612 Investigative [10]
Synonyms
Recombinant flagellin proteins (injectable, radiation induced bone marrow deficiency), Cleveland BioLabs; CBLB-600 series (injectable, radiation sickness), Cleveland BioLabs
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MOA Modulator
External Link
TTD: D04UYT
 Compound Name S-(Dimethylarsenic)Cysteine Investigative [11]
Synonyms
[[(S)-2-Amino-2-carboxyethyl]thio]dimethylarsenic
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MOA Inhibitor
External Link
CID: 46936846
TTD: D08TGY
FA80: Intervertebral disc degeneration 3 Compound(s) Regulating the Disease Click to Show/Hide the Full List
 Compound Name Rexlemestrocel-L Phase 3 [12]
Synonyms
MPC-150-M
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External Link
TTD: DHV2L8
 Compound Name CybroCell Phase 1/2 [13]
External Link
TTD: DS6C1Y
 Compound Name IDCT Phase 1/2 [14]
Synonyms
rebonuputemcel
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External Link
TTD: DK65RJ
References
Ref 1 KMT2A regulates the autophagy-GATA4 axis through METTL3-mediated m(6)A modification of ATG4a to promote NPCs senescence and IVDD progression. Bone Res. 2024 Nov 21;12(1):67. doi: 10.1038/s41413-024-00373-1.
Ref 2 METTL3 Promotes Nucleus Pulposus Cell Senescence in Intervertebral Disc Degeneration by Regulating TLR2 m6A Methylation and Gut Microbiota. J Gerontol A Biol Sci Med Sci. 2024 Aug 1;79(8):glae150. doi: 10.1093/gerona/glae150.
Ref 3 Trial Watch: Experimental Toll-like receptor agonists for cancer therapy. Oncoimmunology. 2012 August 1; 1(5): 699-716.
Ref 4 The novel arthritis-drug substance MCS-18 attenuates the antibody production in vivo. Acta Microbiol Immunol Hung. 2008 Mar;55(1):15-31.
Ref 5 Treatment with OPN-305, a humanized anti-Toll-Like receptor-2 antibody, reduces myocardial ischemia/reperfusion injury in pigs. Circ Cardiovasc Interv. 2012 Apr;5(2):279-87.
Ref 6 Lipoteichoic acid (LTA) of Streptococcus pneumoniae and Staphylococcus aureus activates immune cells via Toll-like receptor (TLR)-2, lipopolysaccha... J Biol Chem. 2003 May 2;278(18):15587-94.
Ref 7 Failure of mycoplasma lipoprotein MALP-2 to induce NK cell activation through dendritic cell TLR2. Microbes Infect. 2011 Apr;13(4):350-8.
Ref 8 Phase I study of OM-174, a lipid A analogue, with assessment of immunological response, in patients with refractory solid tumors. BMC Cancer. 2013 Apr 2;13:172.
Ref 9 Stability and CTL-activity of P40/ELA melanoma vaccine candidate. Biologicals. 2001 Sep-Dec;29(3-4):293-8.
Ref 10 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: 1752).
Ref 11 How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
Ref 12 ClinicalTrials.gov (NCT02412735) Placebo-controlled Study to Evaluate Rexlemestrocel-L Alone or Combined With Hyaluronic Acid in Subjects With Chronic Low Back Pain (MSB-DR003). U.S. National Institutes of Health.
Ref 13 Clinical pipeline report, company report or official report of FibroGenesis.
Ref 14 ClinicalTrials.gov (NCT03955315) Study to Evaluate the Safety and Preliminary Efficacy of IDCT, a Treatment for Symptomatic Lumbar Disc Degeneration. U.S. National Institutes of Health.