m6A-centered Crosstalk Information

Mechanism of Crosstalk between m6A Modification and Epigenetic Regulation
Crosstalk ID
M6ACROT05144
 [1], [2]
Non-coding RNA PCAT6 HNRNPA2B1  lncRNA       miRNA   circRNA Direct Enhancement m6A modification MAPK1 MAPK1 hnRNPA2B1 : m6A sites
m6A Modification:
m6A Regulator Heterogeneous nuclear ribonucleoproteins A2/B1 (HNRNPA2B1) READER
 Regulator Info 
m6A Target Mitogen-activated protein kinase 1 (MAPK/ERK2/MAPK1)
 Targert Gene 
Epigenetic Regulation that have Cross-talk with This m6A Modification:
Epigenetic Regulation Type Non-coding RNA (ncRNA)
Epigenetic Regulator Prostate cancer associated transcript 6 (PCAT6) LncRNA View Details
Regulated Target Heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1) View Details
Crosstalk Relationship ncRNA  →  m6A Enhancement
Crosstalk Mechanism ncRNAs directly impacts m6A modification through recruiting m6A regulator
Crosstalk Summary Mechanically, PCAT6 functions as a scaffold between interferon-stimulated gene 15 (ISG15) and heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1), leading to ISGylation of hnRNPA2B1, thus protecting hnRNPA2B1 from ubiquitination-mediated proteasomal degradation.In breast cancer, modest stable overexpression of A2B1 in MCF-7 cells (MCF-7-A2B1 cells) resulted in tamoxifen and fulvestrant - resistance whereas knockdown of A2B1 in LCC9 and LY2 cells restored tamoxifen and fulvestrant, endocrine-sensitivity. MCF-7-A2B1 cells have increased ER-alpha and reduced miR-222-3p that targets ER-alpha. MCF-7-A2B1 have activated RAC-alpha serine/threonine-protein kinase (AKT1) and Mitogen-activated protein kinase 1 (MAPK/ERK2/MAPK1) that depend on A2B1 expression and are growth inhibited by inhibitors of these pathways.
Responsed Disease Breast cancer ICD-11: 2C60
 Disease Info 
Responsed Drug Tamoxifen
 Drug Info 
Pathway Response MAPK signaling pathway hsa04010
PI3K-Akt signaling pathway hsa04151
Cell Process Cell migration and invasion
In-vitro Model
 MCF-7 Invasive breast carcinoma Homo sapiens CVCL_0031
T-47D Invasive breast carcinoma Homo sapiens CVCL_0553
MDA-MB-231 Breast adenocarcinoma Homo sapiens CVCL_0062
MDA-MB-468 Breast adenocarcinoma Homo sapiens CVCL_0419
HCC1806 Breast squamous cell carcinoma Homo sapiens CVCL_1258
Full List of Potential Compound(s) Related to This m6A-centered Crosstalk
Mitogen-activated protein kinase 1 (MAPK/ERK2/MAPK1) 27 Compound(s) Regulating the Target Click to Show/Hide the Full List
 Compound Name BVD-523 Phase 2 [3]
MOA Modulator
Activity IC50 < 0.3 nM
External Link
CID: 11719003
TTD: D01IED
DrugBank: DB13930
 Compound Name HH2710 Phase 1/2 [4]
MOA Inhibitor
External Link
TTD: D1KIY9
 Compound Name ASTX029 Phase 1/2 [5]
MOA Inhibitor
External Link
TTD: DM1FD5
 Compound Name LY3214996 Phase 1 [6]
Synonyms
JNPRPMBJODOFEC-UHFFFAOYSA-N; 1951483-29-6; GTPL9975; SCHEMBL17837273; MolPort-046-033-624; EX-A2560; BCP19982; CS-6974; HY-101494; LY 3214996; 6,6-dimethyl-2-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-5-(2-morpholin-4-ylethyl)thieno[2,3-c]pyrrol-4-one; 6,6-dimethyl-2-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-5-(2-morpholinoethyl)-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one
    Click to Show/Hide
MOA Inhibitor
External Link
CID: 121408882
TTD: D0TN3Q
 Compound Name VAN-10-4-eluting stent Phase 1 [7]
Synonyms
INC-105-eluting stent, Inncardio/University of Strathclyde; VAN-10-4-eluting stent, University of Strathclyde; Marigold compound (drug-eluting stent, restenosis), Inncardio/University of Strathclyde
    Click to Show/Hide
MOA Inhibitor
External Link
TTD: D08KNG
 Compound Name GDC-0994 Phase 1 [8]
MOA Modulator
Activity IC50 = 3.1 nM
External Link
CID: 71727581
TTD: D0Q4IX
DrugBank: DB15281
 Compound Name JSI-1187 Phase 1 [9]
MOA Inhibitor
External Link
TTD: DBU16T
 Compound Name CHIR-99021 Patented [10]
Synonyms
CHIR99021; CHIR 99021; CT-99021; CT99021
    Click to Show/Hide
MOA Inhibitor
Activity IC50 > 10000 nM
External Link
CID: 9956119
TTD: D0YK9D
 Compound Name COR-D Preclinical [11]
MOA Activator
External Link
TTD: DOJ6D9
 Compound Name SB220025 Terminated [12]
Synonyms
3erk; sb 220025; SB-220025; CHEMBL274064; 165806-53-1; CHEBI:82713; 4-[4-(4-fluorophenyl)-1-(piperidin-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine; 4-(4-FLUOROPHENYL)-1-(4-PIPERIDINYL)-5-(2-AMINO-4-PYRIMIDINYL)-IMIDAZOLE; SB4; 5-(2-Amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-piperidinlyl)imidazole; 4-[5-(4-fluorophenyl)-3-(4-piperidyl)imidazol-4-yl]pyrimidin-2-amine; SB-220025-A; 1-(4-piperidinyl)-4-(4-fluorophenyl)-5-(2-(amino)-4-pyrimidinyl)imidazole
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 19000 nM
External Link
CID: 5164
TTD: D09ICC
DrugBank: DB04338
 Compound Name AEZS-131 Investigative [13]
Synonyms
ERK inhibitor (cancer), AEterna
    Click to Show/Hide
MOA Inhibitor
External Link
TTD: D07NEE
 Compound Name SCH772984 Investigative [14]
Synonyms
SCH-772984
    Click to Show/Hide
MOA Inhibitor
Activity IC50 < 0.3 nM
External Link
CID: 24866313
TTD: D08XVZ
 Compound Name ERK inhibitor III Investigative [15]
Synonyms
AC1NSSSU; 1-nitro-2-[(Z)-[5-(3-nitrophenyl)furan-2-yl]methylideneamino]guanidine
    Click to Show/Hide
MOA Inhibitor
External Link
CID: 5721470
TTD: D0C5AD
 Compound Name (4-Fluoro-phenyl)-(9-methyl-9H-purin-6-yl)-amine Investigative [16]
Synonyms
SCHEMBL6659391
    Click to Show/Hide
MOA Inhibitor
External Link
CID: 11195892
TTD: D0Q1AC
 Compound Name FR-180204 Investigative [17]
Synonyms
865362-74-9; FR 180204; FR180204; ERK Inhibitor II, FR180204; 5-(2-Phenyl-pyrazolo[1,5-a]pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridazin-3-ylamine; CHEMBL259551; 5-(2-PHENYLPYRAZOLO[1,5-A]PYRIDIN-3-YL)-1H-PYRAZOLO[3,4-C]PYRIDAZIN-3-AMINE; C18H13N7; 5-{2-phenylpyrazolo[1,5-a]pyridin-3-yl}-1H-pyrazolo[3,4-c]pyridazin-3-amine; 5-{2-phenylpyrazolo[1,5-a]pyridin-3-yl}-2H-pyrazolo[3,4-c]pyridazin-3-amine; 5-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2H-pyrazolo[3,4-c]pyridazin-3-amine; ERK inhibitor II; MLS002607685
    Click to Show/Hide
MOA Inhibitor
Activity Ki = 310 nM
External Link
CID: 11493598
TTD: D0ZG4G
DrugBank: DB07794
 Compound Name DEBROMOHYMENIALDISINE Investigative [18]
MOA Inhibitor
Activity IC50 = 824 nM
External Link
CID: 135451156
TTD: D01WAI
DrugBank: DB04367
 Compound Name Phosphonothreonine Investigative [12]
Synonyms
phosphothreonine; O-phospho-L-threonine; 1114-81-4; L-Threonine O-phosphate; (2S,3R)-2-amino-3-(phosphonooxy)butanoic acid; O-Phosphothreonine; L-Threonine phosphate; Threoninium dihydrogen phosphate; O-phosphono-L-threonine; L-Threonine O-3-phosphate; O3-phosphothreonine; 27530-80-9; threonine phosphate ester; (2S,3R)-2-amino-3-hydroxybutanoic acid 3-phosphate; Threonine, O-phosphono-; H-Thr(PO3H2)-OH; C4H10NO6P; phospho-l-threonine; EINECS 214-217-5; Synonyms Sources; (S)-2-Amino-3-hydroxybutanoic acid
    Click to Show/Hide
MOA Inhibitor
External Link
CID: 10976469
TTD: D05BHG
DrugBank: DB02482
 Compound Name KT-5720 Investigative [19]
Synonyms
KT 5720; KT5720; 108068-98-0; GTPL337; ZINC3873013; KT 5720, &gt; hexyl (15R,16R,18S)-16-hydroxy-15-methyl-3-oxo-28-oxa-4,14,19-triazaoctacyclo[12.11.2.1^{15,18}.0^{2,6}.0^{7,27}.0^{8,13}.0^{19,26}.0^{20,25}]octacosa-1(26),2(6),7(27),8,10,12,20,22,24-nonaene-16-carboxylate; (9S,10S,12R)-2,3,9,10,11,12-Hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3 inverted exclamation marka,2 inverted exclamation marka,1 inverted exclamation marka-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-c
    Click to Show/Hide
MOA Inhibitor
External Link
CID: 454202
TTD: D0G2VC
 Compound Name Ro31-8220 Investigative [19]
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
    Click to Show/Hide
MOA Inhibitor
External Link
CID: 5083
TTD: D0M5FF
 Compound Name Ro-4396686 Investigative [20]
Synonyms
SCHEMBL5809947; CHEMBL606964
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 12600 nM
External Link
CID: 11396738
TTD: D09XIL
 Compound Name BMS-536924 Investigative [21]
MOA Inhibitor
External Link
CID: 135440466
TTD: D0M4SY
 Compound Name KN-62 Investigative [19]
Synonyms
KN-62 (non-isomeric); GTPL6001; HMS3229A04; CCG-206863
    Click to Show/Hide
MOA Inhibitor
External Link
CID: 5312126
TTD: D0N6ES
 Compound Name CI-1040 Investigative [19]
MOA Inhibitor
External Link
CID: 6918454
TTD: D0B9BU
DrugBank: DB12429
 Compound Name 4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole Investigative [22]
Synonyms
4,5,6,7-tetrabromobenzotriazole
    Click to Show/Hide
MOA Inhibitor
External Link
CID: 1694
TTD: D0O1YH
DrugBank: DB04462
 Compound Name 4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol Investigative [23]
MOA Inhibitor
External Link
CID: 9859248
TTD: D0A5RM
 Compound Name Bisindolylmaleimide-I Investigative [19]
Synonyms
Bisindolylmaleimide i; 133052-90-1; GF 109203X; GF109203X; Go 6850; GF-109203X; RBT205 INHIBITOR; Go-6850; UNII-L79H6N0V6C; Bisindolylmaleimide I (GF 109203X); CHEMBL7463; 3-{1-[3-(DIMETHYLAMINO)PROPYL]-1H-INDOL-3-YL}-4-(1H-INDOL-3-YL)-1H-PYRROLE-2,5-DIONE; 3-(1-(3-(Dimethylamino)propyl)-1H-indol-3-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione; L79H6N0V6C; QMGUOJYZJKLOLH-UHFFFAOYSA-N; 2-[1-(3-dimethylaminopropyl)indol-3-yl]-3-(indol-3-yl)maleimide; GF-109203; Go6850
    Click to Show/Hide
MOA Inhibitor
External Link
CID: 2396
TTD: D0TO6S
DrugBank: DB03777
 Compound Name RO-316233 Investigative [19]
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
    Click to Show/Hide
MOA Inhibitor
External Link
CID: 2399
TTD: D0L8HO
2C60: Breast cancer 2 Compound(s) Regulating the Disease Click to Show/Hide the Full List
 Compound Name Entrectinib Approved [24]
Synonyms
1108743-60-7; RXDX-101; UNII-L5ORF0AN1I; Entrectinib (RXDX-101); L5ORF0AN1I; Benzamide, N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-(4-methyl-1-piperazinyl)-2-[(tetrahydro-2H-pyran-4-yl)amino]-; Benzamide, N-(5-((3,5-difluorophenyl)methyl)-1H-indazol-3-yl)-4-(4-methyl-1-piperazinyl)-2-((tetrahydro-2H-pyran-4-yl)amino)-; Entrectinib [USAN:INN]; YMX; Kinome_2659; Entrectinib(rxdx-101); Entrectinib (USAN/INN); SCHEMBL3512601; GTPL8290; CHEMBL1983268; KS-00000TSK
    Click to Show/Hide
External Link
CID: 25141092
TTD: D0O0LS
DrugBank: DB11986
 Compound Name Everolimus Approved [25]
External Link
CID: 6442177
TTD: D09ZSC
DrugBank: DB01590
References
Ref 1 HnRNPA2B1 ISGylation Regulates m6A-Tagged mRNA Selective Export via ALYREF/NXF1 Complex to Foster Breast Cancer Development. Adv Sci (Weinh). 2024 Jun;11(24):e2307639. doi: 10.1002/advs.202307639. Epub 2024 Apr 16.
Ref 2 HNRNPA2B1 regulates tamoxifen- and fulvestrant-sensitivity and hallmarks of endocrine resistance in breast cancer cells. Cancer Lett. 2021 Oct 10;518:152-168. doi: 10.1016/j.canlet.2021.07.015. Epub 2021 Jul 14.
Ref 3 DOI: 10.1158/1538-7445.AM2015-4693
Ref 4 Clinical pipeline report, company report or official report of HaiHe Biopharma.
Ref 5 Clinical pipeline report, company report or official report of Astex Pharmaceuticals.
Ref 6 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
Ref 7 WO patent application no. 2013,1850,32, Nanotherapeutics for drug targeting.
Ref 8 ERK Mutations Confer Resistance to Mitogen-Activated Protein Kinase Pathway Inhibitors
Ref 9 National Cancer Institute Drug Dictionary (drug name JSI1187).
Ref 10 Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo. Diabetes. 2003 Mar;52(3):588-95. doi: 10.2337/diabetes.52.3.588.
Ref 11 Corchorusin-D directed apoptosis of K562 cells occurs through activation of mitochondrial and death receptor pathways and suppression of AKT/PKB pathway. Cell Physiol Biochem. 2012;30(4):915-26. doi: 10.1159/000341469. Epub 2012 Sep 12.
Ref 12 How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
Ref 13 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: 1495).
Ref 14 Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. Cancer Discov. 2013 Jul;3(7):742-50. doi: 10.1158/2159-8290.CD-13-0070. Epub 2013 Apr 24.
Ref 15 Characterization of ATP-independent ERK inhibitors identified through in silico analysis of the active ERK2 structure. Bioorg Med Chem Lett. 2006 Dec 15;16(24):6281-7. doi: 10.1016/j.bmcl.2006.09.038. Epub 2006 Sep 26.
Ref 16 Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors. J Med Chem. 2005 Feb 10;48(3):710-22. doi: 10.1021/jm0408767.
Ref 17 Crystal structure of human ERK2 complexed with a pyrazolo[3,4-c]pyridazine derivative. Bioorg Med Chem Lett. 2006 Jan 1;16(1):55-8. doi: 10.1016/j.bmcl.2005.09.055. Epub 2005 Oct 18.
Ref 18 Potent inhibition of checkpoint kinase activity by a hymenialdisine-derived indoloazepine. Bioorg Med Chem Lett. 2004 Aug 16;14(16):4319-21. doi: 10.1016/j.bmcl.2004.05.079.
Ref 19 Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000 Oct 1;351(Pt 1):95-105. doi: 10.1042/0264-6021:3510095.
Ref 20 Biological evaluation of a multi-targeted small molecule inhibitor of tumor-induced angiogenesis. Bioorg Med Chem Lett. 2006 Apr 1;16(7):1950-3. doi: 10.1016/j.bmcl.2005.12.092. Epub 2006 Feb 3.
Ref 21 Discovery of a (1H-benzoimidazol-2-yl)-1H-pyridin-2-one (BMS-536924) inhibitor of insulin-like growth factor I receptor kinase with in vivo antitumor activity. J Med Chem. 2005 Sep 8;48(18):5639-43. doi: 10.1021/jm050392q.
Ref 22 Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole. J Med Chem. 2004 Dec 2;47(25):6239-47. doi: 10.1021/jm049854a.
Ref 23 4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects. J Med Chem. 2006 Nov 2;49(22):6500-9. doi: 10.1021/jm0605740.
Ref 24 Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372... Cancer Discov. 2017 Apr;7(4):400-409.
Ref 25 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015