Mechanism of Crosstalk between m6A Modification and Epigenetic Regulation
Crosstalk ID
M6ACROT02228
[1], [2]
DNA methylation DNMT3A METTL14 Direct Inhibition m6A modification CXCR4 CXCR4 METTL14 Methylation : m6A sites
m6A Modification:
m6A Regulator Methyltransferase-like 14 (METTL14) WRITER
m6A Target C-X-C chemokine receptor type 4 (CXCR4)
Epigenetic Regulation that have Cross-talk with This m6A Modification:
Epigenetic Regulation Type DNA methylation (DNAMeth)
Epigenetic Regulator Cysteine methyltransferase DNMT3A (DNMT3A) WRITER View Details
Regulated Target Methyltransferase-like protein 14 (METTL14) View Details
Crosstalk Relationship DNA methylation  →  m6A Inhibition
Crosstalk Mechanism DNA methylation directly impacts m6A modification through modulating the expression level of m6A regulator
Crosstalk Summary lncRNA UCA1 recruited DNA methyltransferase (DNMT1, DNMT3A, and DNMT3B) to the METTL14 promoter region to inhibit METTL14 expression in breast cancer. LNC942-METTL14-C-X-C chemokine receptor type 4 (CXCR4)/CYP1B1 signaling axis, which provides new targets and crosstalk m6A epigenetic modification mechanism for breast cancer prevention and treatment.
Responsed Disease Breast cancer ICD-11: 2C60
Pathway Response Apoptosis hsa04210
Cell Process Cell apoptosis
Full List of Potential Compound(s) Related to This m6A-centered Crosstalk
C-X-C chemokine receptor type 4 (CXCR4) 61 Compound(s) Regulating the Target Click to Show/Hide the Full List
 Compound Name Plerixafor Approved [3]
Synonyms
Mozobil; AMD3100; Amd 3100; JM 2987; JM 3100; JM3100; SDZ SID 791; SID791; AMD-3100; Bicyclam JM-2987; JM-3100; Mozobil (TN); GNA & AMD-3100; HHA & AMD-3100; Plerixafor (INN/USAN); 1,1'-[1,4-Phenylenebis(methylene)]bis[1,4,8,11-tetraazacyclotetradecane]; 1,1'-[1,4-Phenylenebis(methylene)]bis[1,4,8,11-tetraazacyclotetradecane] & Galanthus nivalis agglutinin (GNA); 1,1'-[1,4-Phenylenebis(methylene)]bis[1,4,8,11-tetraazacyclotetradecane] & Hippeastrum hybrid agglutinin(HHA); 1,1'-{1,4-phenylenebis(methylene)}-bis{1,4,8,11-tetraaza-cyclotetradecane}; 1-[[4-(1,4,8,11-tetrazacyclotetradec-1-ylmethyl)phenyl]methyl]-1,4,8,11-tetrazacyclotetradecane
    Click to Show/Hide
MOA Antagonist
Activity IC50 = 0.057 ug.mL-1
External Link
 Compound Name Motixafortide Approved [4]
MOA Antagonist
External Link
 Compound Name Ulocuplumab Phase 3 [5]
MOA Antagonist
External Link
 Compound Name Balixafortide Phase 3 [6]
Synonyms
1051366-32-5; Balixafortide [INN]; UNII-PRC974M49B; PRC974M49B; Ala-cys-ser-ala-pro-arg-tyr-cys-tyr-gln-lys-pro-pro-tyr-his cyclic (2->9)-disulfide; Cyclo(L-alanyl-L-cysteinyl-L-seryl-L-alanyl-D-prolyl-(2S)-2,4-diaminobutanoyl-L-arginyl-L-tyrosyl-L-cysteinyl-L-tyrosyl-L-glutaminyl-L-lysyl-D-prolyl-L-prolyl-L-tyrosyl-L-histidyl), cyclic (2->9)-disulfide
    Click to Show/Hide
MOA Antagonist
External Link
 Compound Name AMD-070 Phase 3 [7]
Synonyms
AMD 070; AMD070; AMD11070; S14-0353; N-(1H-benzoimidazol-2-ylmethyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine; N'-(1H-Benzo[d]imidazol-2-ylmethyl)-N'-(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine Trihydrobromide Dihydrate
    Click to Show/Hide
MOA Antagonist
Activity IC50 = 13 nM
External Link
 Compound Name TG-0054 Phase 2 [8]
Synonyms
CXCR4 binding inhibitor/cell mobilizer (iv, stem cell transplant), TaiGen Biotechnology
    Click to Show/Hide
MOA Inhibitor
External Link
 Compound Name POL-6326 Phase 2 [9]
Synonyms
CXCR4 antagonists, Polyphor; POL-2438; POL-3026; Epitope mimetics (HIV fusion), Polyphor; CXCR4 antagonists (cancer/HIV), Polyphor
    Click to Show/Hide
MOA Antagonist
External Link
 Compound Name CTCE-9908 Phase 1/2 [10]
Synonyms
Anticancer therapy, Chemokine Therapeutics; CTCE-9908/0019
    Click to Show/Hide
MOA Modulator
External Link
 Compound Name USL311 Phase 1/2 [11]
Synonyms
Usl-311; UNII-2BTG5MX2Q2; 2BTG5MX2Q2; SCHEMBL15347153; 2-Pyridinecarboxamide, 6-(hexahydro-4-(1-(1-methylethyl)-4-piperidinyl)-1H-1,4-diazepin-1-yl)-N-4-pyridinyl-; 1373268-67-7
    Click to Show/Hide
MOA Antagonist
External Link
 Compound Name ALX-0651 Phase 1 [12]
Synonyms
Anti-CXCR4 nanobodies (cancer), Ablynx
    Click to Show/Hide
MOA Inhibitor
External Link
 Compound Name CTCE-0214 Phase 1 [13]
Synonyms
CTCE-0013; CTCE-0021; CXCR4 agonists, Chemokine Therapeutics; Stem cell transplant therapy, Chemokine Therapeutics
    Click to Show/Hide
MOA Agonist
External Link
 Compound Name MSX-122 Phase 1 [14]
MOA Antagonist
External Link
 Compound Name PF-06747143 Phase 1 [5]
MOA Antagonist
External Link
 Compound Name BMS-936564 Phase 1 [15]
MOA Modulator
External Link
 Compound Name LY2624587 Phase 1 [16]
MOA Antagonist
External Link
 Compound Name GMI-1359 Phase 1 [17]
MOA Antagonist
External Link
 Compound Name Garnocestim Discontinued in Phase 1 [18]
Synonyms
SB-251353
    Click to Show/Hide
MOA Modulator
External Link
 Compound Name SURADISTA Discontinued in Phase 1 [19]
Synonyms
PNU-145156E; FCE-26644 (formerly); PNU-151484 (Na salt); 7,7'-[Carbonylbis[imino(1-methyl-1H-pyrrole-4,2-diyl)carbonylimino(1-methyl-1H-pyrrole-4,2-diyl)carbonylimino]]bis-1,3-naphthalenedisulfonic acid tetrapotassium salt; 7,7-Ureylene-bis(1-methyl-4,2-pyrrolecarboxamido)bis(1-methyl-4,2-pyrrolecarboxamido)bis(1,3-naphthalenedisulfonic acid) tetrapotassium salt
    Click to Show/Hide
MOA Modulator
External Link
 Compound Name MAb173 Preclinical [20]
MOA Antagonist
External Link
 Compound Name KRH-2731 Terminated [21]
MOA Binder
External Link
 Compound Name Cyclo(-D-Tyr-L-Arg-L-MeArg-L-Nal-Gly-) Investigative [22]
Synonyms
CHEMBL436536
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 99 nM
External Link
 Compound Name Cyclo(-D-MeTyr-D-Arg-L-Arg-L-Nal-Gly-) Investigative [22]
Synonyms
CHEMBL375993
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 157 nM
External Link
 Compound Name Cyclo(-D-Tyr-D-MeArg-L-Arg-L-Nal-Gly-) Investigative [22]
Synonyms
CHEMBL218806
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 3 nM
External Link
 Compound Name GSK-812397 Investigative [23]
Synonyms
CXCR4 receptor antagonists (HIV-1 infection); CXCR4 receptor antagonists (HIV-1 infection), GlaxoSmithKline
    Click to Show/Hide
MOA Antagonist
Activity IC50 = 0.87 nM
External Link
 Compound Name AT-009 Investigative [23]
MOA Antagonist
External Link
 Compound Name Cyclo(-D-Tyr-D-Arg-L-Arg-L-MeNal-Gly-) Investigative [22]
Synonyms
CHEMBL426169
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 563 nM
External Link
 Compound Name Cyclo(-D-Tyr-L-Arg-L-Arg-L-Nal-L-Ala-) Investigative [22]
Synonyms
CHEMBL387120
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 170 nM
External Link
 Compound Name Cyclo(-D-Tyr-L-MeArg-L-Arg-L-Nal-Gly-) Investigative [22]
Synonyms
CHEMBL374421
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 23 nM
External Link
 Compound Name Cyclo(-D-Tyr-Arg-Arg-Nal-Gly-) Investigative [24]
Synonyms
Fc-131; FC131; CHEMBL436283; FC 131; 606968-52-9; CHEMBL2180076; AC1NQNK6; SCHEMBL15987252; ZINC3925712; Cyclo(-Nal-Gly-D-Tyr-Arg-Arg-); BDBM50399002; BDBM50166106; KB-272560; B7647; N-{3-[(2S,5S,8S,14R)-5-(3-Guanidino-propyl)-14-(4-hydroxy-benzyl)-8-naphthalen-2-ylmethyl-3,6,9,12,15-pentaoxo-1,4,7,10,13pentaaza-cyclopentadec-2-yl]-propyl}-guanidine
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 4 nM
External Link
 Compound Name Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-beta-Ala-) Investigative [22]
Synonyms
CHEMBL219135
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 350 nM
External Link
 Compound Name KUR-CXCR4 Investigative [23]
MOA Modulator
External Link
 Compound Name isothiourea-1t Investigative [25]
Synonyms
IT1t
    Click to Show/Hide
MOA Antagonist
Activity IC50 = 8 nM
External Link
 Compound Name Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-Sar-) Investigative [22]
Synonyms
CHEMBL374862
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 256 nM
External Link
 Compound Name CX-02 Investigative [23]
Synonyms
CX-05; CXCR4 monoclonal antibodies (cancer); CXCR4 monoclonal antibodies (cancer), Northwest Biotherapeutics; CXCR4 therapeutics (cancer), Northwest Biotherapeutics
    Click to Show/Hide
External Link
 Compound Name isothiourea-1a Investigative [25]
Synonyms
IT1a
    Click to Show/Hide
MOA Antagonist
Activity IC50 = 11 nM
External Link
 Compound Name ND-401 Investigative [23]
Synonyms
ND-4019; CCR5 and CXCR4 inhibitors (HIV infection), NeED Pharmaceuticals
    Click to Show/Hide
MOA Inhibitor
External Link
 Compound Name CXCR4 gene disrupted T cells Investigative [23]
Synonyms
CXCR4 gene disrupted T cells (HIV infection)
    Click to Show/Hide
MOA Modulator
External Link
 Compound Name T134 Investigative [26]
Synonyms
GTPL852
    Click to Show/Hide
MOA Antagonist
External Link
 Compound Name Cyclo(-D-Tyr-L-Arg-L-Arg-L-Ala-Sar-) Investigative [22]
Synonyms
CHEMBL219075
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 167 nM
External Link
 Compound Name Cyclo(-D-Tyr-D-Arg-L-MeArg-L-Nal-Gly-) Investigative [22]
Synonyms
CHEMBL376219
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 21 nM
External Link
 Compound Name ATI-2341 Investigative [23]
Synonyms
ATI-2346; ATI-2756; ATI-2766; CXCR4 agonists (cancer/bone marrow transplantation), Ascent; Pepducins (cancer/bone marrow transplantation), Ascent
    Click to Show/Hide
MOA Agonist
External Link
 Compound Name Cyclo(-D-Tyr-L-Arg-L-Arg-L-MeNal-Gly-) Investigative [22]
Synonyms
CHEMBL375850
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 250 nM
External Link
 Compound Name Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-L-Ala-) Investigative [22]
Synonyms
CHEMBL376811
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 92 nM
External Link
 Compound Name Cyclo(-D-Tyr-D-Ala-L-Arg-L-Nal-Gly-) Investigative [22]
Synonyms
CHEMBL384429
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 230 nM
External Link
 Compound Name T140 Investigative [26]
Synonyms
[L-3-(2-naphthyl)-alanine3]-T134
    Click to Show/Hide
MOA Antagonist
External Link
 Compound Name Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-D-Ala-) Investigative [22]
Synonyms
CHEMBL373636
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 11 nM
External Link
 Compound Name Cyclo(-D-Ala-D-Arg-L-Arg-L-Nal-Gly-) Investigative [22]
Synonyms
CHEMBL373440
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 130 nM
External Link
 Compound Name CTCE-0324 Investigative [23]
Synonyms
Vascular disease therapeutic, Chemokine Therapeutics
    Click to Show/Hide
MOA Modulator
External Link
 Compound Name Cyclo(-D-Tyr-L-Ala-L-Arg-L-Nal-Gly-) Investigative [22]
Synonyms
CHEMBL374108
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 63 nM
External Link
 Compound Name Cyclo(-D-Tyr-L-Arg-L-Arg-L-Nal-beta-Ala-) Investigative [22]
Synonyms
CHEMBL375991
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 47 nM
External Link
 Compound Name Cyclo(-D-Tyr-L-Arg-L-Arg-L-Nal-Gly-) Investigative [22]
Synonyms
CHEMBL219474
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 4 nM
External Link
 Compound Name LP-0067 Investigative [23]
Synonyms
CXCR4 antagonists (autoimmune disease); CXCR4 antagonists (autoimmune disease), Leo Pharma
    Click to Show/Hide
MOA Antagonist
External Link
 Compound Name NB-325 Investigative [23]
Synonyms
PEHMB; Polyethylene hexamethylene biguanide
    Click to Show/Hide
MOA Modulator
External Link
 Compound Name Cyclo(-D-MeTyr-L-Arg-L-Arg-L-Nal-Gly-) Investigative [22]
Synonyms
CHEMBL219096
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 128 nM
External Link
 Compound Name Cyclo(-D-Tyr-L-Arg-L-Arg-L-Nal-D-Ala-) Investigative [22]
Synonyms
CHEMBL375990
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 11 nM
External Link
 Compound Name Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-L-Pic-) Investigative [22]
Synonyms
CHEMBL373637
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 640 nM
External Link
 Compound Name T22 Investigative [26]
Synonyms
[Tyr5,12,Lys7]-polyphemusin II
    Click to Show/Hide
MOA Antagonist
External Link
 Compound Name TN-14003 Investigative [27]
Synonyms
UNII-1TW3FT746I; 1TW3FT746I; TN14003; BDBM194584; US9205085, MSX-207; H-Arg-Arg-Nal-Cys-Tyr-Cit-Lys-DLys-Pro-Tyr-Arg-Cit-Cys-Arg-NH2; L-Argininamide, L-arginyl-L-arginyl-3-(2-naphthalenyl)-L-alanyl-L-cysteinyl-L-tyrosyl-N5-(aminocarbonyl)-L-ornithyl-L-lysyl-D-lysyl-L-prolyl-L-tyrosyl-L-arginyl-N5-(aminocarbonyl)-L-ornithyl-L-cysteinyl-, cyclic (4->13)-disulfide
    Click to Show/Hide
MOA Inhibitor
External Link
 Compound Name Cyclo(-D-Tyr-D-Arg-L-Arg-L-Nal-Gly-) Investigative [22]
Synonyms
CHEMBL219339
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 8 nM
External Link
 Compound Name CXCL8 Investigative [28]
Synonyms
Interleukin-8; CHEMBL411250; IL-8
    Click to Show/Hide
MOA Agonist
External Link
 Compound Name viral macrophage inflammatory protein-II Investigative [29]
Synonyms
CFLTKRGRQVC; vMIP-II; AC1LAF0N; GTPL768; vMIP-II (RESIDUE 41-51, CYCLIC); (4R,7S,10S,13S,19S,22S,25S,28S,31S,34R)-34-amino-22-(4-aminobutyl)-10-(3-amino-3-oxopropyl)-31-benzyl-13,19-bis[3-(diaminomethylideneamino)propyl]-25-[(1R)-1-hydroxyethyl]-28-(2-methylpropyl)-6,9,12,15,18,21,24,27,30,33-decaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29,32-decazacyclopentatriacontane-4-carboxylic acid
    Click to Show/Hide
MOA Antagonist
External Link
Cysteine methyltransferase DNMT3A (DNMT3A) 8 Compound(s) Regulating the Target Click to Show/Hide the Full List
 Compound Name PMID27376512-Compound-Figure3CN Patented [30]
MOA Inhibitor
Activity EC50 = 1100 nM
External Link
 Compound Name PMID27376512-Compound-Figure3CG Patented [30]
MOA Inhibitor
Activity EC50 = 2400 nM
External Link
 Compound Name PMID27376512-Compound-Figure3CM Patented [30]
MOA Inhibitor
Activity EC50 = 1100 nM
External Link
 Compound Name PMID27376512-Compound-Figure2aExample1 Patented [30]
MOA Inhibitor
Activity IC50 = 3000 nM
External Link
 Compound Name PMID27376512-Compound-MTC-424 Patented [30]
MOA Inhibitor
Activity IC50 = 1940 nM
External Link
 Compound Name PMID27376512-Compound-MTC-427 Patented [30]
MOA Inhibitor
Activity IC50 = 295 nM
External Link
 Compound Name PMID27376512-Compound-MTC-422 Patented [30]
MOA Inhibitor
Activity IC50 = 1430 nM
External Link
 Compound Name PMID27376512-Compound-MTC-423 Patented [30]
MOA Inhibitor
Activity IC50 = 363 nM
External Link
2C60: Breast cancer 2 Compound(s) Regulating the Disease Click to Show/Hide the Full List
 Compound Name Entrectinib Approved [31]
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
 Compound Name Everolimus Approved [32]
External Link
References
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Ref 2 LNC942 promoting METTL14-mediated m(6)A methylation in breast cancer cell proliferation and progression. Oncogene. 2020 Jul;39(31):5358-5372. doi: 10.1038/s41388-020-1338-9. Epub 2020 Jun 23.
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Ref 8 CXCR4 Antagonist TG-0054 Mobilizes Mesenchymal Stem Cells, Attenuates Inflammation, and Preserves Cardiac Systolic Function in a Porcine Model of Myocardial Infarction. Cell Transplant. 2015;24(7):1313-28. doi: 10.3727/096368914X681739. Epub 2014 May 12.
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Ref 10 A CXCR4 antagonist CTCE-9908 inhibits primary tumor growth and metastasis of breast cancer. J Surg Res. 2009 Aug;155(2):231-6. doi: 10.1016/j.jss.2008.06.044. Epub 2008 Aug 9.
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Ref 15 BMS-936564/MDX-1338: a fully human anti-CXCR4 antibody induces apoptosis in vitro and shows antitumor activity in vivo in hematologic malignancies. Clin Cancer Res. 2013 Jan 15;19(2):357-66. doi: 10.1158/1078-0432.CCR-12-2333. Epub 2012 Dec 4.
Ref 16 Inhibition of CXCR4 by LY2624587, a Fully Humanized Anti-CXCR4 Antibody Induces Apoptosis of Hematologic Malignancies. PLoS One. 2016 Mar 8;11(3):e0150585. doi: 10.1371/journal.pone.0150585. eCollection 2016.
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Ref 21 Progress in targeting HIV-1 entry. Drug Discov Today. 2005 Aug 15;10(16):1085-94. doi: 10.1016/S1359-6446(05)03550-6.
Ref 22 Structure-activity relationships of cyclic peptide-based chemokine receptor CXCR4 antagonists: disclosing the importance of side-chain and backbone functionalities. J Med Chem. 2007 Jan 25;50(2):192-8. doi: 10.1021/jm0607350.
Ref 23 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: 71).
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Ref 25 Orally bioavailable isothioureas block function of the chemokine receptor CXCR4 in vitro and in vivo. J Med Chem. 2008 Dec 25;51(24):7915-20. doi: 10.1021/jm801065q.
Ref 26 A low-molecular-weight inhibitor against the chemokine receptor CXCR4: a strong anti-HIV peptide T140. Biochem Biophys Res Commun. 1998 Dec 30;253(3):877-82. doi: 10.1006/bbrc.1998.9871.
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Ref 28 Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: prevention of reperfusion injury. Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11791-6. doi: 10.1073/pnas.0402090101. Epub 2004 Jul 28.
Ref 29 A broad-spectrum chemokine antagonist encoded by Kaposi's sarcoma-associated herpesvirus. Science. 1997 Sep 12;277(5332):1656-9. doi: 10.1126/science.277.5332.1656.
Ref 30 DNA methyltransferase inhibitors: an updated patent review (2012-2015). Expert Opin Ther Pat. 2016 Sep;26(9):1017-30. doi: 10.1080/13543776.2016.1209488. Epub 2016 Jul 18.
Ref 31 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 32 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015