Details of the Drug Combination

General Information of Drug Combination (ID: DCJZS8T)

• Drug Combination Name: Vemurafenib + Thioguanine
• Indication: Invasive ductal carcinoma; Status: Investigative [1]
• Component Drugs:
  Vemurafenib (DM62UG5): Small molecular drug
  Thioguanine (DM7NKEV): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: BT-549
  Zero Interaction Potency (ZIP) Score: 9.36
  Bliss Independence Score: 9.69
  Loewe Additivity Score: 1.78
  LHighest Single Agent (HSA) Score: 7.73

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Vemurafenib

Disease Entry	ICD 11	Status	REF
Melanoma	2C30	Approved	[2]

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]

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	[9]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[10]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[10]

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	[11]

Vemurafenib Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Microphthalmia-associated transcription factor (MITF)	OT6XJCZH	MITF_HUMAN	Affects Expression	[7]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[12]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[13]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[8]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[8]
CD70 antigen (CD70)	OTHB2AL1	CD70_HUMAN	Decreases Expression	[14]
Melanocyte protein PMEL (PMEL)	OTCDDHHM	PMEL_HUMAN	Increases Expression	[7]
Melanoma antigen recognized by T-cells 1 (MLANA)	OT1N2S2K	MAR1_HUMAN	Increases Expression	[7]

Indication(s) of Thioguanine

Disease Entry	ICD 11	Status	REF
Acute lymphocytic leukaemia	2B33.3	Approved	[3]
Acute myelogenous leukaemia	2A41	Approved	[4]
Acute myeloid leukaemia	2A60	Approved	[5]
Middle East Respiratory Syndrome (MERS)	1D64	Preclinical	[6]
Severe acute respiratory syndrome (SARS)	1D65	Preclinical	[6]

Thioguanine Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
MERS-CoV papain-like proteinase (PL-PRO)	TTYJOLE	R1AB_CVEMC (854-2740)	Inhibitor	[6]
Inosine-5'-monophosphate dehydrogenase (IMPDH)	TTCAQMW	NOUNIPROTAC	Intercalator	[15]
SARS-CoV papain-like proteinase (PL-PRO)	TTRGHB2	R1AB_CVHSA (819-2740)	Inhibitor	[6]

Thioguanine Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[16]
Multidrug resistance-associated protein 4 (ABCC4)	DTCSGPB	MRP4_HUMAN	Substrate	[17]
Concentrative Na(+)-nucleoside cotransporter 3 (SLC28A3)	DT4YL5R	S28A3_HUMAN	Substrate	[18]

Thioguanine Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Thiopurine methyltransferase (TPMT)	DEFQ8VO	TPMT_HUMAN	Metabolism	[19]
Hypoxanthine phosphoribosyltransferase (HPRT1)	DEVXTP5	HPRT_HUMAN	Metabolism	[20]

Thioguanine Interacts with 3 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Occludin (OCLN)	OTSUTVWL	OCLN_HUMAN	Decreases Activity	[21]
ATP-binding cassette sub-family C member 5 (ABCC5)	OT34G4US	MRP5_HUMAN	Decreases Response To Substance	[22]
Baculoviral IAP repeat-containing protein 2 (BIRC2)	OTFXFREP	BIRC2_HUMAN	Decreases Response To Substance	[23]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Breast adenocarcinoma	DCQR9IC	MDA-MB-468	Investigative	[1]
Carcinoma	DCW8OW1	RXF 393	Investigative	[1]
Carcinoma	DC5UC31	MCF7	Investigative	[1]
Colon adenocarcinoma	DCANGXD	COLO 205	Investigative	[1]
Invasive ductal carcinoma	DCYSPML	T-47D	Investigative	[1]
Invasive ductal carcinoma	DCNPQSN	HS 578T	Investigative	[1]
Adenocarcinoma	DCB2BQ4	DU-145	Investigative	[24]
Amelanotic melanoma	DCVCSDD	MDA-MB-435	Investigative	[24]
Astrocytoma	DCVJGOT	U251	Investigative	[24]
Astrocytoma	DCLL0E6	SNB-19	Investigative	[24]
Chronic myelogenous leukemia	DC2WI1N	K-562	Investigative	[24]
Clear cell renal cell carcinoma	DC5FT5P	786-0	Investigative	[24]
Clear cell renal cell carcinoma	DCPQ4N4	CAKI-1	Investigative	[24]
Cutaneous melanoma	DCMCAMO	SK-MEL-5	Investigative	[24]
Glioblastoma	DC5QA30	SNB-75	Investigative	[24]
Glioma	DC8DZL7	SF-295	Investigative	[24]
Glioma	DCJ5CCN	SF-539	Investigative	[24]
High grade ovarian serous adenocarcinoma	DCGF7QX	OVCAR-8	Investigative	[24]
High grade ovarian serous adenocarcinoma	DC8T9WI	NCI\\/ADR-RES	Investigative	[24]
Lung adenocarcinoma	DCVTBS0	EKVX	Investigative	[24]
Malignant melanoma	DCTYLNY	LOX IMVI	Investigative	[24]
Melanoma	DC2G8CE	UACC-257	Investigative	[24]
Ovarian serous cystadenocarcinoma	DCTIEM3	SK-OV-3	Investigative	[24]
Papillary renal cell carcinoma	DCSHACK	ACHN	Investigative	[24]
Plasma cell myeloma	DCKTI38	RPMI-8226	Investigative	[24]
Renal cell carcinoma	DCFRRS4	SN12C	Investigative	[24]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1126165
• [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: 5893).
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [4] Thioguanine FDA Label
• [5] 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: 6845).
• [6] Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus. Antiviral Res. 2015 Mar;115:9-16.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013 Mar 15;19(6):1458-66.
• [11] Vemurafenib for the treatment of melanoma. Expert Opin Pharmacother. 2012 Dec;13(17):2533-43.
• [12] Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells. Elife. 2015 Aug 18;4:e04640. doi: 10.7554/eLife.04640.
• [13] 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.
• [14] 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.
• [15] Immune effector cells produce lethal DNA damage in cells treated with a thiopurine. Cancer Res. 2009 Mar 15;69(6):2393-9.
• [16] ABC transporters and their role in nucleoside and nucleotide drug resistance. Biochem Pharmacol. 2012 Apr 15;83(8):1073-83.
• [17] Multidrug resistance protein 4 (MRP4/ABCC4) mediates efflux of bimane-glutathione. Int J Biochem Cell Biol. 2004 Feb;36(2):247-57.
• [18] Involvement of the concentrative nucleoside transporter 3 and equilibrative nucleoside transporter 2 in the resistance of T-lymphoblastic cell lines to thiopurines. Biochem Biophys Res Commun. 2006 Apr 28;343(1):208-15.
• [19] Usefulness of thiopurine methyltransferase and thiopurine metabolite analysis in clinical practice in patients with inflammatory bowel diseases. Acta Gastroenterol Belg. 2010 Jul-Sep;73(3):331-5.
• [20] Qualitative and quantitative difference in mutation induction between carbon- and neon-ion beams in normal human cells. Biol Sci Space. 2003 Dec;17(4):302-6.
• [21] The thiopurine methyltransferase genetic polymorphism is associated with thioguanine-related veno-occlusive disease of the liver in children with acute lymphoblastic leukemia. Clin Pharmacol Ther. 2006 Oct;80(4):375-83. doi: 10.1016/j.clpt.2006.07.002.
• [22] The multidrug resistance protein 5 (ABCC5) confers resistance to 5-fluorouracil and transports its monophosphorylated metabolites. Mol Cancer Ther. 2005 May;4(5):855-63.
• [23] Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias. Clin Cancer Res. 2000 May;6(5):1796-803.
• [24] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125976