General Information of Drug Combination (ID: DCEJAV2)

Drug Combination Name
Dexrazoxane Vemurafenib
Indication
Disease Entry Status REF
Adenocarcinoma Investigative [1]
Component Drugs Dexrazoxane   DMD7X1O Vemurafenib   DM62UG5
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL
High-throughput Screening Result Testing Cell Line: A549
Zero Interaction Potency (ZIP) Score: 3.05
Bliss Independence Score: 4.39
Loewe Additivity Score: 0.17
LHighest Single Agent (HSA) Score: 3.89

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
Indication(s) of Dexrazoxane
Disease Entry ICD 11 Status REF
Breast cancer 2C60-2C65 Approved [2]
Chemoprotection N.A. Approved [3]
Inflammatory breast cancer 2C62 Approved [4]
Respiratory tract disease CB7Z Investigative [5]
Dexrazoxane Interacts with 2 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
DNA topoisomerase II beta (TOP2B) TT4NVEM TOP2B_HUMAN Inhibitor [7]
DNA topoisomerase II (TOP2) TT0IHXV TOP2A_HUMAN; TOP2B_HUMAN Modulator [8]
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Dexrazoxane Interacts with 1 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Dihydropyrimidinase-related protein 1 (DRP1) DE0EUXB DPYL1_HUMAN Metabolism [9]
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Dexrazoxane Interacts with 1 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
DNA topoisomerase 2-alpha (TOP2A) OT6LPS08 TOP2A_HUMAN Decreases Activity [10]
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Indication(s) of Vemurafenib
Disease Entry ICD 11 Status REF
Melanoma 2C30 Approved [6]
Vemurafenib Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Serine/threonine-protein kinase B-raf (BRAF) TTWCGQT BRAF_HUMAN Modulator [3]
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Vemurafenib Interacts with 3 DTP Molecule(s)
DTP Name DTP ID UniProt ID Mode of Action REF
P-glycoprotein 1 (ABCB1) DTUGYRD MDR1_HUMAN Substrate [13]
Organic anion transporting polypeptide 1B1 (SLCO1B1) DT3D8F0 SO1B1_HUMAN Substrate [14]
Organic anion transporting polypeptide 1B3 (SLCO1B3) DT9C1TS SO1B3_HUMAN Substrate [14]
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Vemurafenib Interacts with 1 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) DE4LYSA CP3A4_HUMAN Metabolism [15]
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Vemurafenib Interacts with 19 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Microphthalmia-associated transcription factor (MITF) OT6XJCZH MITF_HUMAN Affects Expression [11]
Myc proto-oncogene protein (MYC) OTPV5LUK MYC_HUMAN Decreases Expression [16]
Cyclin-dependent kinase 4 (CDK4) OT7EP05T CDK4_HUMAN Decreases Expression [17]
C-C motif chemokine 2 (CCL2) OTAD2HEL CCL2_HUMAN Increases Expression [18]
G1/S-specific cyclin-D1 (CCND1) OT8HPTKJ CCND1_HUMAN Decreases Expression [17]
Mitogen-activated protein kinase 3 (MAPK3) OTCYKGKO MK03_HUMAN Decreases Phosphorylation [12]
Mitogen-activated protein kinase 1 (MAPK1) OTH85PI5 MK01_HUMAN Decreases Phosphorylation [12]
CD70 antigen (CD70) OTHB2AL1 CD70_HUMAN Decreases Expression [19]
Prostaglandin G/H synthase 2 (PTGS2) OT75U9M4 PGH2_HUMAN Decreases Expression [17]
Sterol regulatory element-binding protein 1 (SREBF1) OTWBRPAI SRBP1_HUMAN Decreases Expression [20]
Melanocyte protein PMEL (PMEL) OTCDDHHM PMEL_HUMAN Increases Expression [11]
Melanoma-associated antigen 1 (MAGEA1) OTXAO193 MAGA1_HUMAN Decreases Expression [11]
Thyroxine 5-deiodinase (DIO3) OTNTITOT IOD3_HUMAN Decreases Expression [21]
Melanoma antigen recognized by T-cells 1 (MLANA) OT1N2S2K MAR1_HUMAN Increases Expression [11]
Hypoxia-inducible factor 1-alpha (HIF1A) OTADSC03 HIF1A_HUMAN Increases Expression [18]
GTPase KRas (KRAS) OT78QCN8 RASK_HUMAN Affects Response To Substance [22]
Serine/threonine-protein kinase B-raf (BRAF) OT7S81XQ BRAF_HUMAN Increases Response To Substance [23]
Heat shock 70 kDa protein 1A (HSPA1A) OTKGIE76 HS71A_HUMAN Decreases Response To Substance [24]
GTPase NRas (NRAS) OTVQ1DG3 RASN_HUMAN Affects Response To Substance [22]
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⏷ Show the Full List of 19 DOT(s)

Test Results of This Drug Combination in Other Disease Systems

Indication DrugCom ID Cell Line Status REF
Adenocarcinoma DC5YFHX HCT116 Investigative [1]
Minimally invasive lung adenocarcinoma DCJVUY4 NCI-H322M Investigative [1]
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References

1 Loss of function mutations in VARS encoding cytoplasmic valyl-tRNA synthetase cause microcephaly, seizures, and progressive cerebral atrophy.Hum Genet. 2018 Apr;137(4):293-303. doi: 10.1007/s00439-018-1882-3. Epub 2018 Apr 24.
2 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: 7330).
3 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
4 Dexrazoxane FDA Label
5 Design and development of antisense drugs. Expert Opin. Drug Discov. 2008 3(10):1189-1207.
6 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: 5893).
7 How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
8 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
9 Metabolism of the cardioprotective drug dexrazoxane and one of its metabolites by isolated rat myocytes, hepatocytes, and blood. Drug Metab Dispos. 2005 Jun;33(6):719-25.
10 Investigation of novel dexrazoxane analogue JR-311 shows significant cardioprotective effects through topoisomerase IIbeta but not its iron chelating metabolite. Toxicology. 2017 Dec 1;392:1-10. doi: 10.1016/j.tox.2017.09.012. Epub 2017 Sep 21.
11 PLX4032 Mediated Melanoma Associated Antigen Potentiation in Patient Derived Primary Melanoma Cells. J Cancer. 2015 Oct 29;6(12):1320-30. doi: 10.7150/jca.11126. eCollection 2015.
12 Actin remodeling confers BRAF inhibitor resistance to melanoma cells through YAP/TAZ activation. EMBO J. 2016 Mar 1;35(5):462-78. doi: 10.15252/embj.201592081. Epub 2015 Dec 14.
13 Differential effects of the oncogenic BRAF inhibitor PLX4032 (vemurafenib) and its progenitor PLX4720 on ABCB1 function. J Pharm Pharm Sci. 2014;17(1):154-68.
14 Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013 Mar 15;19(6):1458-66.
15 Vemurafenib for the treatment of melanoma. Expert Opin Pharmacother. 2012 Dec;13(17):2533-43.
16 Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells. Elife. 2015 Aug 18;4:e04640. doi: 10.7554/eLife.04640.
17 Role of the protein kinase BRAF in the pathogenesis of endometriosis. Expert Opin Ther Targets. 2016 Aug;20(8):1017-29. doi: 10.1080/14728222.2016.1180367. Epub 2016 May 4.
18 Overcoming melanoma resistance to vemurafenib by targeting CCL2-induced miR-34a, miR-100 and miR-125b. Oncotarget. 2016 Jan 26;7(4):4428-41. doi: 10.18632/oncotarget.6599.
19 Melanoma Expressed-CD70 Is Regulated by RhoA and MAPK Pathways without Affecting Vemurafenib Treatment Activity. PLoS One. 2016 Feb 1;11(2):e0148095. doi: 10.1371/journal.pone.0148095. eCollection 2016.
20 Sustained SREBP-1-dependent lipogenesis as a key mediator of resistance to BRAF-targeted therapy. Nat Commun. 2018 Jun 27;9(1):2500. doi: 10.1038/s41467-018-04664-0.
21 MAPK and SHH pathways modulate type 3 deiodinase expression in papillary thyroid carcinoma. Endocr Relat Cancer. 2016 Mar;23(3):135-46. doi: 10.1530/ERC-15-0162.
22 Paradoxical activation of MEK/ERK signaling induced by B-Raf inhibition enhances DR5 expression and DR5 activation-induced apoptosis in Ras-mutant cancer cells. Sci Rep. 2016 May 25;6:26803. doi: 10.1038/srep26803.
23 The BRAFT1799A mutation confers sensitivity of thyroid cancer cells to the BRAFV600E inhibitor PLX4032 (RG7204). Biochem Biophys Res Commun. 2011 Jan 28;404(4):958-62. doi: 10.1016/j.bbrc.2010.12.088. Epub 2010 Dec 23.
24 HSP70 Inhibition Limits FAK-Dependent Invasion and Enhances the Response to Melanoma Treatment with BRAF Inhibitors. Cancer Res. 2016 May 1;76(9):2720-30. doi: 10.1158/0008-5472.CAN-15-2137. Epub 2016 Mar 16.