Mechanism of Crosstalk between m6A Modification and Epigenetic Regulation
Crosstalk ID
M6ACROT03592
[1], [2]
Histone modification H3K4me3 SMYD2 LINC01605 Indirect Enhancement m6A modification CCNE1 CCNE1 METTL3 Methylation : m6A sites
m6A Modification:
m6A Regulator Methyltransferase-like 3 (METTL3) WRITER
m6A Target G1/S-specific cyclin-E1 (CCNE1)
Epigenetic Regulation that have Cross-talk with This m6A Modification:
Epigenetic Regulation Type Histone modification (HistMod)
Epigenetic Regulator N-lysine methyltransferase SMYD2 (SMYD2) WRITER View Details
Regulated Target Histone H3 lysine 4 trimethylation (H3K4me3) View Details
Downstream Gene LINC01605 View Details
Crosstalk Relationship Histone modification  →  m6A Enhancement
Crosstalk Mechanism histone modification indirectly regulates m6A modification through downstream signaling pathways
Crosstalk Summary LINC01605 was regulated by SMYD2-EP300-mediated modifications of histone Histone H3 lysine 4 trimethylation (H3K4me3) as well as H3K27ac. LINC01605 was found to bind to METTL3 and promote the m6A modification of SPTBN2 mRNA, thereby facilitating the translation of SPTBN2. METTL3 promotes colorectal cancer proliferation by stabilizing G1/S-specific cyclin-E1 (CCNE1) mRNA in an m6A-dependent manner, representing a promising therapeutic strategy for the treatment of CRC.
Responsed Disease Colorectal cancer ICD-11: 2B91
Pathway Response Cell cycle hsa04110
Cell Process Cell proliferation
Arrest cell cycle at G1 phase
In-vitro Model
HT29 Colon cancer Mus musculus CVCL_A8EZ
LoVo Colon adenocarcinoma Homo sapiens CVCL_0399
In-vivo Model LoVo cells (5 × 106 cells/ 200 uL PBS) stably transfected with METTL3 knockdown lentiviral vector or control vector were respectively injected subcutaneously into the left flank of each mouse.
Full List of Potential Compound(s) Related to This m6A-centered Crosstalk
G1/S-specific cyclin-E1 (CCNE1) 25 Compound(s) Regulating the Target Click to Show/Hide the Full List
 Compound Name PD-0183812 Terminated [3]
Synonyms
PETCVZZPKYJZAU-UHFFFAOYSA-N; PD183812; AC1NS8PJ; CHEMBL139653; SCHEMBL5268115; BDBM6280; PD 0183812; N8 Pyrido[2,3-d]pyrimidin-7-one deriv 72; 8-{bicyclo[221]heptan-2-yl}-2-({4-[4-(3-hydroxypropyl)piperidin-1-yl]phenyl}amino)-7H,8H-pyrido[2,3-d]pyrimidin-7-one; 8-(3-bicyclo[221]heptanyl)-2-[4-[4-(3-hydroxypropyl)piperidin-1-yl]anilino]pyrido[2,3-d]pyrimidin-7-one; PD0183813
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MOA Inhibitor
External Link
 Compound Name (2'Z,3'E)-5-Chloro-5'-chloro-indirubin-3'-oxime Investigative [4]
MOA Inhibitor
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 Compound Name (2'Z,3'E)-5-Chloro-5'-methyl-indirubin-3'-oxime Investigative [4]
MOA Inhibitor
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 Compound Name (2'Z,3'E)-5-Fluoro-5'-methoxy-indirubin-3'-oxime Investigative [4]
MOA Inhibitor
External Link
 Compound Name (2'Z,3'E)-5-Fluoro-5'-fluoro-indirubin-3'-oxime Investigative [4]
MOA Inhibitor
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 Compound Name (2'Z,3'E)-5-Fluoro-5'-chloro-indirubin-3'-oxime Investigative [4]
MOA Inhibitor
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 Compound Name (2'Z,3'E)-5-Chloro-5'-fluoro-indirubin-3'-oxime Investigative [4]
MOA Inhibitor
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 Compound Name 2-((3,5-diamino-1H-pyrazol-4-yl)diazenyl)phenol Investigative [5]
MOA Inhibitor
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 Compound Name 5-nitroindirubin-3'-oxime Investigative [4]
MOA Inhibitor
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 Compound Name (2'Z,3'E)-5-Nitro-5'-methyl-indirubin-3'-oxime Investigative [4]
MOA Inhibitor
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 Compound Name (2'Z,3'E)-5-Nitro-5'-chloro-indirubin-3'-oxime Investigative [4]
MOA Inhibitor
External Link
 Compound Name (2'Z,3'E)-5-Fluoro-5'-hydroxy-indirubin-3'-oxime Investigative [4]
MOA Inhibitor
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 Compound Name (2'Z,3'E)-5-Chloro-5'-hydroxy-indirubin-3'-oxime Investigative [4]
MOA Inhibitor
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 Compound Name (2'Z,3'E)-5-Nitro-5'-fluoro-indirubin-3'-oxime Investigative [4]
MOA Inhibitor
External Link
 Compound Name (2'Z,3'E)-5-Nitro-5'-methoxy-indirubin-3'-oxime Investigative [4]
MOA Inhibitor
External Link
 Compound Name (2'Z,3'E)-5-Fluoro-5'-methyl-indirubin-3'-oxime Investigative [4]
MOA Inhibitor
External Link
 Compound Name (2'Z,3'E)-5-Nitro-5'-hydroxy-indirubin-3'-oxime Investigative [4]
MOA Inhibitor
External Link
 Compound Name 3-((3,5-diamino-1H-pyrazol-4-yl)diazenyl)phenol Investigative [5]
MOA Inhibitor
External Link
 Compound Name aloisine A Investigative [6]
Synonyms
4-(7-butyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)phenol; 496864-16-5; RP107; 6-PHENYL[5H]PYRROLO[2,3-B]PYRAZINE; CHEMBL75680; 7-n-Butyl-6-(4-hydroxyphenyl)[5H]pyrrolo[2,3-b]pyrazine; RP-107; ALH; 4-{7-butyl-5H-pyrrolo[2,3-b]pyrazin-6-yl}phenol; 1ung; SCHEMBL80147; BDBM7377; GTPL5924; AC1NS169; 4-(7-Butyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)-phenol; CHEBI:93641; CTK8D4068; DTXSID30416115; HMS3229A14; RM-39; BCP26893; ZINC2540737; ACT06534; IN1539; HSCI1_000219; MFCD04973541; AKOS005145972; CCG-206814; DB07364; RTC-063070; AJ-39131
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MOA Inhibitor
External Link
 Compound Name 3-(indole-3-yl)-4-phenyl-1H-pyrrole-2,5-dione Investigative [7]
Synonyms
CHEMBL380598; SCHEMBL3148490; HVQJGNALTWNDMX-UHFFFAOYSA-N; BDBM50375058; 2-(1H-Indole-3-yl)-3-phenylmaleimide
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MOA Inhibitor
External Link
 Compound Name BMS-536924 Investigative [8]
MOA Inhibitor
External Link
 Compound Name 3,4-di-(4-methoxyphenyl)-1H-pyrrole-2,5-dione Investigative [7]
Synonyms
1H-Pyrrole-2,5-dione, 3,4-bis(4-methoxyphenyl)-; 108774-82-9; ACMC-20mbs9; CHEMBL381099; CTK0G2626; DTXSID90449388
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MOA Inhibitor
External Link
 Compound Name 3,4-diphenyl-1H-pyrrole-2,5-dione Investigative [7]
Synonyms
2,3-diphenylmaleimide; 1H-Pyrrole-2,5-dione, 3,4-diphenyl-; 31295-36-0; AC1MBL6S; SCHEMBL114611; CHEMBL201949; CTK1B9880; 3,4-diphenylpyrrole-2,5-dione; DTXSID70372903; ZINC3847556
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MOA Inhibitor
External Link
 Compound Name 3-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-2,5-dione Investigative [7]
Synonyms
CHEMBL372076; SCHEMBL3822337
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MOA Inhibitor
External Link
 Compound Name 4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol Investigative [5]
MOA Inhibitor
External Link
N-lysine methyltransferase SMYD2 (SMYD2) 6 Compound(s) Regulating the Target Click to Show/Hide the Full List
 Compound Name AZ505 Preclinical [9]
Synonyms
AZ 505; AZ-505
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MOA Inhibitor
Activity IC50 = 120 nM
External Link
 Compound Name LLY-507 Preclinical [10]
Synonyms
1793053-37-8; LLY507; CHEMBL3414623; 5-Cyano-2'-{4-[2-(3-Methyl-1h-Indol-1-Yl)ethyl]piperazin-1-Yl}-N-[3-(Pyrrolidin-1-Yl)propyl]biphenyl-3-Carboxamide; 3-cyano-5-(2-{4-[2-(3-methyl-1H-indol-1-yl)ethyl]piperazin-1-yl}phenyl)-N-[3-(pyrrolidin-1-yl)propyl]benzamide; 3-Cyano-5-[2-[4-[2-(3-methyl-1H-indol-1-yl)ethyl]piperazin-1-yl]phenyl]-N-[3-(pyrrolidin-1-yl)propyl]benzamide; GTPL8239; SCHEMBL19760400; EX-A899; LLY 507; MolPort-042-624-530; BCP17114; s7575; BDBM50075102; ZINC231558920; AKOS027470175; CS-5126
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MOA Inhibitor
Activity IC50 < 15 nM
External Link
 Compound Name EPZ032597 Preclinical [11]
MOA Inhibitor
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 Compound Name EPZ033294 Preclinical [11]
MOA Inhibitor
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 Compound Name A-893 Preclinical [12]
Synonyms
1868232-32-9; (R)-N-cyclohexyl-3-((3,4-dichlorophenethyl)amino)-N-(2-((2-hydroxy-2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethyl)amino)ethyl)propanamide; CHEMBL3590526; N-Cyclohexyl-N~3~-[2-(3,4-Dichlorophenyl)ethyl]-N-(2-{[(2r)-2-Hydroxy-2-(3-Oxo-3,4-Dihydro-2h-1,4-Benzoxazin-8-Yl)ethyl]amino}ethyl)-Beta-Alaninamide; SCHEMBL17476248; EX-A2769; BDBM50095537; AKOS030235552; ZINC230499113; ACN-037539; AC-29886; HY-19563; CS-0015655; Q27454706; 4GQ; N-Cyclohexyl-3-[2-(3,4-dichlorophenyl)ethylamino]-N-[2-[[(2R)-2-hydroxy-2-(3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]ethyl]propanamide
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MOA Inhibitor
External Link
 Compound Name BAY 598 Preclinical [13]
Synonyms
BAY-598; 1906919-67-2; CHEMBL3818617; 1906919-67-2 (S-isomer); (S,E)-N-(1-(N'-cyano-N-(3-(difluoromethoxy)phenyl)carbamimidoyl)-3-(3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-4-yl)-N-ethyl-2-hydroxyacetamide; BAY 598 - Bio-X; BAY598; GTPL8953; EX-A1835; BDBM50180955; ZINC504786915; AC-31567; BS-16389; HY-19546; CS-0015642; J3.601.000B; Q27074893; (S)-N-(1-(N'-Cyano-N-(3-(difluoromethoxy)phenyl)carbamimidoyl)-3-(3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-4-yl)-N-ethyl-2-hydroxyacetamide; (S,E)-N-(1-(N-cyano-N'-(3-(difluoromethoxy)phenyl)carbamimidoyl)-3-(3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-4-yl)-N-ethyl-2-hydroxyacetamide; (S,Z)-N-(1-(N-cyano-N'-(3-(difluoromethoxy)phenyl)carbamimidoyl)-3-(3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-4-yl)-N-ethyl-2-hydroxyacetamide; N-[(4S)-1-[(Cyanoamino)[[3-(difluoromethoxy)phenyl]imino]methyl]-3-(3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-4-yl]-N-ethyl-2-hydroxyacetamide; N-[(4S)-1-[(Z)-N'-cyano-N-[3-(difluoromethoxy)phenyl]carbamimidoyl]-3-(3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-4-yl]-N-ethyl-2-hydroxyacetamide
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MOA Inhibitor
External Link
2B91: Colorectal cancer 25 Compound(s) Regulating the Disease Click to Show/Hide the Full List
 Compound Name Retifanlimab Approved [14]
Synonyms
INCMGA0012; Retifanlimab
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External Link
 Compound Name Aflibercept Approved [15]
Synonyms
Ziv-Aflibercept; Zaltrap (TN); VEGF Trap; VEGF Trap-Eye
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External Link
 Compound Name Regorafenib Approved [16]
Synonyms
755037-03-7; BAY 73-4506; Regorafenibum; Stivarga; 4-(4-(3-(4-Chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)-N-methylpicolinamide; BAY73-4506; Regorafenib (BAY 73-4506); UNII-24T2A1DOYB; 4-[4-({[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide; BAY-73-4506; 24T2A1DOYB; CHEMBL1946170; CHEBI:68647; Stivarga (TN); BAY73-4506 hydrochloride; Regorafenib [USAN:INN]
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External Link
 Compound Name Bevacizumab Approved [17]
Synonyms
Bevacizumab (ophthalmic slow-release tissue tablet)
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External Link
 Compound Name SYM-004 Phase 3 [17]
Synonyms
Chimeric IgG1 antibody 1024 (cancer), Symphogen; Chimeric IgG1 antibody 992 (cancer), Symphogen; Chimeric IgG1 antibodies992 + 1024 (cancer), Symphogen
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External Link
 Compound Name Bevacizumab + Erlotinib Phase 3 [18]
External Link
 Compound Name CPI-613 Phase 3 [17]
Synonyms
95809-78-2; 6,8-bis(benzylthio)octanoic acid; CPI 613; MLS006010202; SCHEMBL1062218; 6,8-Bis(benzylsulfanyl)octanoic acid; Octanoic acid, 6,8-bis((phenylmethyl)thio)-; Octanoic acid, 6,8-bis[(phenylMethyl)thio]-; 6,8-Bis[(phenylmethyl)thio]octanoic acid; CPI613; CHEMBL3186849; QCR-193; AOB1058; MolPort-023-219-128; HMS3656L06; C22H28O2S2; BCP04663; EX-A2043; s2776; AKOS025142095; BCP9000552; DB12109; RL06062; CS-0961; NCGC00344764-01; SMR004701300; AS-16613; BC261916; AK174899; HY-15453; BCP0726000030; KB-293127; AB0035874
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External Link
 Compound Name Bevacizumab Approved [15]
External Link
 Compound Name AlloStim Phase 2/3 [19]
Synonyms
AlloStim (TN)
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External Link
 Compound Name Sibrotuzumab Phase 2 [20]
External Link
 Compound Name CV301 Phase 2 [21]
External Link
 Compound Name Efatutazone Phase 2 [22]
Synonyms
Inolitazone; 223132-37-4; 5-[[4-[[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-yl]methoxy]phenyl]methyl]-2,4-Thiazolidinedione; Efatutazone [INN]; RS5444; CS-7017; SCHEMBL3246054; CHEMBL3545280; JCYNMRJCUYVDBC-UHFFFAOYSA-N; Efatutazone;CS-7017;RS5444; BCP07478; AKOS030526729; DB11894; CS-0778; KB-77905; DA-07988; HY-14792; QC-10456; 4CA-1384; FT-0737589; 5-[4-[6-(4-amino-3 ,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione
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External Link
 Compound Name LOR-2040 Phase 2 [23]
External Link
 Compound Name RG7221 Phase 2 [24]
External Link
 Compound Name PEG-SN38 Phase 2 [25]
Synonyms
EZN-2208
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External Link
 Compound Name MEGF0444A Phase 2 [26]
External Link
 Compound Name Encapsulated cell therapy Phase 1/2 [27]
External Link
 Compound Name AB928 Phase 1/2 [28]
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 Compound Name MGD007 Phase 1 [24]
External Link
 Compound Name BNC-101 Phase 1 [29]
External Link
 Compound Name Navicixizumab Phase 1 [17]
External Link
 Compound Name RG7160 Discontinued in Phase 2 [30]
External Link
 Compound Name Nimesulide Terminated [31]
Synonyms
51803-78-2; N-(4-Nitro-2-phenoxyphenyl)methanesulfonamide; Mesulid; Flogovital; Sulidene; Nimed; R-805; 4-NITRO-2-PHENOXYMETHANESULFONANILIDE; Nisulid; Nimesulidum [INN-Latin]; Nimesulida [INN-Spanish]; R 805; UNII-V4TKW1454M; 4-Nitro-2-phenoxy-methanesulfonanilide; 4'-Nitro-2'-phenoxymethanesulfonanilide; Methanesulfonamide, N-(4-nitro-2-phenoxyphenyl)-; EINECS 257-431-4; 4'-Nitro-2'-phenoxymethansulfonanilid; BRN 2421175; CHEMBL56367; MLS000069680; V4TKW1454M; Methanesulfonanilide, 4'-nitro-2'-phenoxy-; CHEBI:44445; Dulanermin
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External Link
 Compound Name Saracatinib Phase 2 [32]
External Link
 Compound Name G3139 + Irinotecan Investigative [33]
External Link
References
Ref 1 LINC01605, regulated by the EP300-SMYD2 complex, potentiates the binding between METTL3 and SPTBN2 in colorectal cancer. Cancer Cell Int. 2021 Sep 20;21(1):504. doi: 10.1186/s12935-021-02180-8.
Ref 2 Methyltransferase like 3 promotes colorectal cancer proliferation by stabilizing CCNE1 mRNA in an m6A-dependent manner. J Cell Mol Med. 2020 Mar;24(6):3521-3533. doi: 10.1111/jcmm.15042. Epub 2020 Feb 10.
Ref 3 Pyrido[2,3-d]pyrimidin-7-one inhibitors of cyclin-dependent kinases. J Med Chem. 2000 Nov 30;43(24):4606-16. doi: 10.1021/jm000271k.
Ref 4 5,5'-substituted indirubin-3'-oxime derivatives as potent cyclin-dependent kinase inhibitors with anticancer activity. J Med Chem. 2010 May 13;53(9):3696-706. doi: 10.1021/jm100080z.
Ref 5 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 6 Aloisines, a new family of CDK/GSK-3 inhibitors. SAR study, crystal structure in complex with CDK2, enzyme selectivity, and cellular effects. J Med Chem. 2003 Jan 16;46(2):222-36. doi: 10.1021/jm020319p.
Ref 7 Design, synthesis, and biological evaluation of 3,4-diarylmaleimides as angiogenesis inhibitors. J Med Chem. 2006 Feb 23;49(4):1271-81. doi: 10.1021/jm0580297.
Ref 8 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 9 Structural basis of substrate methylation and inhibition of SMYD2. Structure. 2011 Sep 7;19(9):1262-73.
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: 2714).
Ref 11 Epigenetics and beyond: targeting writers of protein lysine methylation to treat disease. Nat Rev Drug Discov. 2021 Apr;20(4):265-286. doi: 10.1038/s41573-020-00108-x. Epub 2021 Jan 19.
Ref 12 Discovery of A-893, A New Cell-Active Benzoxazinone Inhibitor of Lysine Methyltransferase SMYD2. ACS Med Chem Lett. 2015 Apr 29;6(6):695-700.
Ref 13 Discovery and Characterization of a Highly Potent and Selective Aminopyrazoline-Based in Vivo Probe (BAY-598) for the Protein Lysine Methyltransferase SMYD2. J Med Chem. 2016 May 26;59(10):4578-600.
Ref 14 Development of Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Signaling Pathway.J Med Chem. 2019 Feb 28;62(4):1715-1730.
Ref 15 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
Ref 16 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. (Ligand id: 5891).
Ref 17 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
Ref 18 ClinicalTrials.gov (NCT00130728) A Study to Evaluate the Efficacy of Bevacizumab in Combination With Tarceva for Advanced Non-Small Cell Lung Cancer
Ref 19 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
Ref 20 ClinicalTrials.gov (NCT02198274) Intravenous BIBH 1 in Patients With Metastatic Colorectal Cancer. U.S. National Institutes of Health.
Ref 21 ClinicalTrials.gov (NCT03547999) A Trial of Perioperative CV301 Vaccination in Combination With Nivolumab and Systemic Chemotherapy for Metastatic CRC. U.S. National Institutes of Health.
Ref 22 ClinicalTrials.gov (NCT02152137) Efatutazone With Paclitaxel Versus Paclitaxel Alone in Treating Patients With Advanced Anaplastic Thyroid Cancer. U.S. National Institutes of Health.
Ref 23 ClinicalTrials.gov (NCT00087165) GTI-2040, Docetaxel, and Prednisone in Treating Patients With Prostate Cancer. U.S. National Institutes of Health.
Ref 24 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
Ref 25 ClinicalTrials.gov (NCT01036113) A Phase 2 Study of EZN-2208 in Patients With Metastatic Breast Cancer. U.S. National Institutes of Health.
Ref 26 ClinicalTrials.gov (NCT00909740) A Study of the Safety and Pharmacokinetics of MEGF0444A Administered to Patients With Advanced Solid Tumors. U.S. National Institutes of Health.
Ref 27 VC-01's Path to the Clinic. Viacyte. 2015.
Ref 28 ClinicalTrials.gov (NCT04660812) An Open Label Study Evaluating the Efficacy and Safety of AB928 Based Treatment Combinations in Patients With Metastatic Colorectal Cancer.. U.S. National Institutes of Health.
Ref 29 ClinicalTrials.gov (NCT02726334) A Phase I, Dose Escalation Study of BNC101 in Patients With Metastatic Colorectal Cancer.. U.S. National Institutes of Health.
Ref 30 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029052)
Ref 31 Clinical pipeline report, company report or official report of Genentech (2011).
Ref 32 Phase II Study of Saracatinib (AZD0530) in Patients With Previously Treated Metastatic Colorectal Cancer. Invest New Drugs. 2015 Aug;33(4):977-84.
Ref 33 Design and development of antisense drugs. Expert Opin. Drug Discov. 2008 3(10):1189-1207.