m6A-centered Crosstalk Information

Mechanism of Crosstalk between m6A Modification and Epigenetic Regulation
Crosstalk ID
M6ACROT05973
 [1]
Histone modification H3K4me3 KDM5A WTAP Direct Inhibition m6A modification LncRNA NORAD LncRNA NORAD WTAP Methylation : m6A sites
m6A Modification:
m6A Regulator Wilms tumor 1-associating protein (WTAP) WRITER
 Regulator Info 
m6A Target Long intergenic non-protein coding RNA 657 (NORAD)
 Targert Gene 
Epigenetic Regulation that have Cross-talk with This m6A Modification:
Epigenetic Regulation Type Histone modification (HistMod)
Epigenetic Regulator Lysine-specific demethylase 5A (KDM5A) ERASER View Details
Regulated Target Histone H3 lysine 4 trimethylation (H3K4me3) View Details
Downstream Gene WTAP View Details
Crosstalk Relationship Histone modification  →  m6A Inhibition
Crosstalk Mechanism Histone modification directly impacts m6A modification through modulating the level of m6A regulator
Crosstalk Summary LncRNA Long intergenic non-protein coding RNA 657 (NORAD) could be modified by m6A due to an increase in WTAP, which was regulated by KDM5A-mediated Histone H3 lysine 4 trimethylation (H3K4me3) modification of the promoter. YTHDF2-mediated decay of NORAD is enhanced in senescent NPCs, and then deficiency of NORAD results in less sequestraion of PUMILIO proteins, contributing to the augmented activity of PUM1 and PUM2, thus repressing the expression of target E2F3 mRNAs and promoting the cellular senescence.
Responsed Disease Intervertebral disc degeneration ICD-11: FA80
 Disease Info 
In-vitro Model
 Nucleus pulposus cells (NPCs) (Nucleus pulposus cells)
In-vivo Model After 50g male NORAD-KO or C57 mice at age of 8 weeks were anesthetized with 3% (w/v) pentobarbital (2 ml/kg) and grouped randomly, investigators blinded to the group allocation performed the experiment. The disc levels in rat tail (Co6/7, 7/8, and 8/9) were located by palpation on the coccygeal vertebrae and confirmed by trial radiography. Needles (33-G) were used to puncture the annulus fibrosus layer though the tail skin, in parallel to the end plates. To ensure that the needle did not penetrate too deeply , the length of the needle was pre-determined according to the dimensions of annulus fibrosus and the NP , which were measured in a preliminary experiment and found to be approximately 4 mm. Five kinds of solution were prepared for intradisc injection, including AA V vector, AAV containing shPUM1, AAV containing shPUM2 for Norad KO mice, AAV vector, AAV containing shE2F3, AAVcontaining OE-E2F3 for WT mice.
Full List of Potential Compound(s) Related to This m6A-centered Crosstalk
Lysine-specific demethylase 5A (KDM5A) 21 Compound(s) Regulating the Target Click to Show/Hide the Full List
 Compound Name 6EP Patented [2]
Synonyms
2-{5-[(4-Chloro-2-Methylphenyl)methoxy]-1h-Pyrazol-1-Yl}pyridine-4-Carboxylic Acid; 1613410-75-5; CHEMBL3786952; SCHEMBL15778339; BDBM191600; NCGC00390881-02; QC3611,QC-3611,QC 3611; 2-(5-((4-chloro-2-methylbenzyl)oxy)-1Hpyrazol-1-yl)isonicotinic acid (N19)
    Click to Show/Hide
MOA Inhibitor
Activity IC50 < 100nM
External Link
CID: 74766595
TTD: D00SUC
 Compound Name BDBM50158803 Patented [3]
Synonyms
CHEMBL3787438; SCHEMBL15792889
    Click to Show/Hide
MOA Inhibitor
Activity IC50 < 100nM
External Link
CID: 90216982
TTD: D01WHH
 Compound Name US10022354, Example 151 Patented [4]
Synonyms
SCHEMBL19513974; CHEMBL4060968; BDBM281211
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 0.065 nM
External Link
CID: 132054530
TTD: D03POM
 Compound Name US9714230, 12 Patented [2]
Synonyms
SCHEMBL15778399; LKBZHRSAENXIOI-UHFFFAOYSA-N; BDBM263942; 2-(5-p-tolyl-1H-pyrazol-1- yl)isonicotinic acid; 2-(5-p-tolyl-1H-pyrazol-1-yl)isonicotinic acid
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 550 nM
External Link
CID: 76901247
TTD: D03TKM
 Compound Name BDBM50158791 Patented [5]
Synonyms
CHEMBL3786596; SCHEMBL15818867; SCHEMBL19646964
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 550 nM
External Link
CID: 77106319
TTD: D05CCY
 Compound Name US10040779, Example 4 Patented [6]
Synonyms
SCHEMBL15792083; BDBM277707; 3-[(5-chloro-1-methyl-1H-indazol-3-yl)amino]pyridine-4-carboxylic acid
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MOA Inhibitor
Activity IC50 < 0.1nM
External Link
CID: 75202257
TTD: D06TKT
 Compound Name US9611221, Example 9 Patented [7]
Synonyms
3-[(biphenyl-4-ylmethyl)amino]pyridine-4-carboxylic acid; SCHEMBL15286753; RNBCOBWQQCESLL-UHFFFAOYSA-N; BDBM314105
    Click to Show/Hide
MOA Inhibitor
Activity IC50 < 100nM
External Link
CID: 71766727
TTD: D09CWB
 Compound Name US9714230, 46 Patented [8]
Synonyms
SCHEMBL15778753; MITOFELVTHNBGA-UHFFFAOYSA-N; BDBM263981; 2-(5-(4-bromophenyl)-1H-pyrazol- 1-yl)isonicotinic acid; 2-[5-(4-bromophenyl)-1H-pyrazol-1-yl]pyridine-4-carboxylic acid
    Click to Show/Hide
MOA Inhibitor
Activity IC50 < 10nM
External Link
CID: 86725517
TTD: D0F3TL
 Compound Name BDBM50158794 Patented [6]
Synonyms
CHEMBL3785470; SCHEMBL15792416
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MOA Inhibitor
Activity IC50 < 0.1nM
External Link
CID: 76282772
TTD: D0G8QR
 Compound Name BDBM50158703 Patented [2]
Synonyms
CHEMBL3785832; SCHEMBL15777940
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MOA Inhibitor
Activity IC50 < 100nM
External Link
CID: 90204862
TTD: D0GH8J
 Compound Name AKOS020330656 Patented [9]
Synonyms
CHEMBL3774545; SCHEMBL15820618; RFUZGPWCXINBNW-UHFFFAOYSA-N; BDBM50153334; ZINC123452149; 3-{[(5-methylthiophen-2-yl)methyl]amino}pyridine-4-carboxylic acid
    Click to Show/Hide
MOA Inhibitor
Activity IC50 < 100nM
External Link
CID: 77106317
TTD: D0HT9Q
 Compound Name BDBM50158755 Patented [10]
Synonyms
CHEMBL3786579; SCHEMBL15778210
    Click to Show/Hide
MOA Inhibitor
Activity IC50 < 100nM
External Link
CID: 90205053
TTD: D0K4LW
 Compound Name US10174026, Example 99 Patented [11]
Synonyms
SCHEMBL16157351; BDBM320432; 2-(pyrrolidin-1-ylcarbonyl)-1H- pyrrolo[3,2-b]pyridine-7- carboxylic acid
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MOA Inhibitor
Activity IC50 < 100nM
External Link
CID: 85469291
TTD: D0N9JZ
 Compound Name AKOS020330481 Patented [7]
Synonyms
3-[(4-methoxybenzyl)amino]pyridine-4-carboxylic acid; SCHEMBL4855920; US9611221, Example 7; XKZFNTZMCLZYHZ-UHFFFAOYSA-N; BDBM314103; 3[(4-methoxybenzyl)amino]pyridine-4-carboxylic acid
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 550 nM
External Link
CID: 59699608
TTD: D0NG8M
 Compound Name US10022354, Example 5 Patented [4]
Synonyms
SCHEMBL17682496; CHEMBL4062756; BDBM281065
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 7.4 nM
External Link
CID: 121279569
TTD: D0NM3B
 Compound Name NCGC00381656-01 Patented [12]
Synonyms
CHEMBL4100530; SCHEMBL16157407; BDBM320423; US10174026, Example 88; 2-[(2-chlorophenyl)-propoxy- methyl]-1H-pyrrolo[3,2-b]- pyridine-7-carboxylic acid
    Click to Show/Hide
MOA Inhibitor
Activity IC50 < 100nM
External Link
CID: 117637389
TTD: D0PQ5P
 Compound Name US10174026, Example 2 Patented [11]
Synonyms
SCHEMBL16149258; FEZIKLVLFANZBD-UHFFFAOYSA-N; BDBM320362; 2-phenyl-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid; 2-phenyl-1H-pyrrolo[3,2-b] pyridine-7-carboxylic acid
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 550 nM
External Link
CID: 86280871
TTD: D0R2GT
 Compound Name US10022354, Example 152 Patented [4]
Synonyms
CHEMBL4059597; SCHEMBL17682668; BDBM281212
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 0.083 nM
External Link
CID: 121279737
TTD: D0T8YT
 Compound Name US10040779, Example 1 Patented [6]
Synonyms
SCHEMBL15792304; BDBM277704; 3-[(1-methyl-1H-indazol-3-yl)amino]pyridine-4-carboxylic acid
    Click to Show/Hide
MOA Inhibitor
Activity IC50 < 0.1nM
External Link
CID: 76282043
TTD: D0VZ5E
 Compound Name 1190312-92-5 Patented [11]
Synonyms
3-chloro-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid; 3-CHLORO-4-AZAINDOLE-7-CARBOXYLIC ACID; SCHEMBL16157363; US10174026, Example 1; UAFNSWUBMGTOQA-UHFFFAOYSA-N; BDBM320361; ZINC44713035; 3-chloro-1H-pyrrolo[3,2-b] pyridine-7-carboxylic acid
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 5500 nM
External Link
CID: 53412620
TTD: D0ZJ0Z
 Compound Name PBIT Investigative [13]
Synonyms
2514-30-9; 2-(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one; 2-(4-methylphenyl)-1,2-benzothiazol-3-one; MLS000583746; 2-(p-Tolyl)benzo[d]isothiazol-3(2H)-one; 2-(p-tolyl)-1,2-benzothiazol-3-one; SMR000200989; 2-(4-methylphenyl)-1,2-benzothiazol-3(2H)-one; 1,2-Benzisothiazol-3(2H)-one, 2-(4-methylphenyl)-; 2-(4-methylphenyl)-2,3-dihydro-1,2-benzothiazol-3-one; ChemDiv3_007090; AC1LIP69; cid_935415; SCHEMBL2443755; GTPL7026; CHEMBL1336959; CTK0J4356; BDBM34737; AOB6896; DTXSID10359056; MolPort-002-285-696; HMS2576N21
    Click to Show/Hide
MOA Inhibitor
External Link
CID: 935415
TTD: D0IQ7Y
FA80: Intervertebral disc degeneration 3 Compound(s) Regulating the Disease Click to Show/Hide the Full List
 Compound Name Rexlemestrocel-L Phase 3 [14]
Synonyms
MPC-150-M
    Click to Show/Hide
External Link
TTD: DHV2L8
 Compound Name CybroCell Phase 1/2 [15]
External Link
TTD: DS6C1Y
 Compound Name IDCT Phase 1/2 [16]
Synonyms
rebonuputemcel
    Click to Show/Hide
External Link
TTD: DK65RJ
References
Ref 1 WTAP-mediated m(6)A modification of lncRNA NORAD promotes intervertebral disc degeneration. Nat Commun. 2022 Mar 18;13(1):1469. doi: 10.1038/s41467-022-28990-6.
Ref 2 Histone demethylase inhibitors. US9714230.
Ref 3 Histone demethylase inhibitors. US9617242.
Ref 4 IRE-1 inhibitors
Ref 5 Histone demethylase inhibitors. US9725441.
Ref 6 Histone demethylase inhibitors. US10040779.
Ref 7 Histone demethylase inhibitors. US9611221.
Ref 8 Histone demethylase inhibitors. US9604961.
Ref 9 Histone demethylase inhibitors. US10179769.
Ref 10 Histone demethylase inhibitors. US10173996.
Ref 11 Histone demethylase inhibitors. US10174026.
Ref 12 Histone demethylase inhibitors. US9738637.
Ref 13 Identification of small molecule inhibitors of Jumonji AT-rich interactive domain 1B (JARID1B) histone demethylase by a sensitive high throughput screen. J Biol Chem. 2013 Mar 29;288(13):9408-17. doi: 10.1074/jbc.M112.419861. Epub 2013 Feb 13.
Ref 14 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 15 Clinical pipeline report, company report or official report of FibroGenesis.
Ref 16 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.