Details of the Drug Combination

General Information of Drug Combination (ID: DCT4EJR)

• Drug Combination Name: Vismodegib + Dacarbazine
• Indication: Amelanotic melanoma; Status: Investigative [1]
• Component Drugs:
  Vismodegib (DM5IXKQ): Small molecular drug
  Dacarbazine (DMNPZL4): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: M14
  Zero Interaction Potency (ZIP) Score: 4.96
  Bliss Independence Score: 9
  Loewe Additivity Score: 2.43
  LHighest Single Agent (HSA) Score: 5.41

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Vismodegib

Disease Entry	ICD 11	Status	REF
Basal cell carcinoma	2C32	Approved	[2]
Primitive neuroectodermal tumour medulloblastoma	2A00.11	Phase 2	[3]

Vismodegib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Smoothened homolog (SMO)	TT8J1S3	SMO_HUMAN	Modulator	[6]

Vismodegib Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[7]

Vismodegib Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Tumor necrosis factor receptor superfamily member 10A (TNFRSF10A)	OTBPCU2O	TR10A_HUMAN	Increases Expression	[8]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[8]
Zinc finger protein GLI1 (GLI1)	OT1BTAJO	GLI1_HUMAN	Decreases Expression	[8]
Zinc finger protein GLI2 (GLI2)	OTIRV97L	GLI2_HUMAN	Decreases Expression	[8]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[8]
Platelet-derived growth factor receptor alpha (PDGFRA)	OTDJXUCN	PGFRA_HUMAN	Decreases Expression	[8]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[8]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[8]
Protein patched homolog 1 (PTCH1)	OTMG07H5	PTC1_HUMAN	Decreases Expression	[8]
Protein smoothened (SMO)	OTXXE208	SMO_HUMAN	Decreases Expression	[8]
Protein patched homolog 2 (PTCH2)	OTOQ0K9V	PTC2_HUMAN	Decreases Expression	[8]
Suppressor of fused homolog (SUFU)	OT0IRYG1	SUFU_HUMAN	Decreases Response To Substance	[9]
N-myc proto-oncogene protein (MYCN)	OTWD33K1	MYCN_HUMAN	Decreases Response To Substance	[9]

Indication(s) of Dacarbazine

Disease Entry	ICD 11	Status	REF
Adenocarcinoma	2D40	Approved	[4]
Astrocytoma	2A00.0Y	Approved	[4]
Brain disease	8C70-8E61	Approved	[4]
Central nervous system disease	8A04-8D87	Approved	[4]
Glioblastoma	2A00	Approved	[4]
Gliosarcoma	N.A.	Approved	[4]
Melanoma	2C30	Approved	[5]
Classic Hodgkin lymphoma	N.A.	Investigative	[4]
Neuroblastoma	2D11.2	Investigative	[4]

Dacarbazine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human Deoxyribonucleic acid (hDNA)	TTUTN1I	NOUNIPROTAC	Breaker	[11]

Dacarbazine Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[12]
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Metabolism	[13]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[14]

Dacarbazine Interacts with 12 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Increases Expression	[15]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[10]
Interferon regulatory factor 1 (IRF1)	OT43DI6J	IRF1_HUMAN	Increases Expression	[16]
Methylated-DNA--protein-cysteine methyltransferase (MGMT)	OT40A9WH	MGMT_HUMAN	Decreases Activity	[17]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Response To Substance	[18]
DNA repair nuclease/redox regulator APEX1 (APEX1)	OT53OI14	APEX1_HUMAN	Increases Response To Substance	[19]
Solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1)	OTA675TJ	GTR1_HUMAN	Decreases Response To Substance	[20]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Response To Substance	[21]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Response To Substance	[21]
Clusterin (CLU)	OTQGG0JM	CLUS_HUMAN	Affects Response To Substance	[22]
Mitogen-activated protein kinase kinase kinase 1 (MAP3K1)	OTS3FVTY	M3K1_HUMAN	Decreases Response To Substance	[21]
Erythropoietin (EPO)	OTZ90CN4	EPO_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	DCV2VIA	MDA-MB-468	Investigative	[24]
Invasive ductal carcinoma	DC3XAYX	HS 578T	Investigative	[24]
Amelanotic melanoma	DCE4NUQ	MDA-MB-435	Investigative	[1]
Clear cell renal cell carcinoma	DC3THBN	786-0	Investigative	[1]
Clear cell renal cell carcinoma	DCVKDT0	TK-10	Investigative	[1]
Cutaneous melanoma	DCTSAHK	SK-MEL-28	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCGAI45	OVCAR-8	Investigative	[1]
Large cell lung carcinoma	DCWQXDO	NCI-H460	Investigative	[1]
Lung adenocarcinoma	DC8UAGZ	HOP-62	Investigative	[1]
Lung adenocarcinoma	DCKVFKJ	NCI-H522	Investigative	[1]
Non-small cell lung carcinoma	DC42FR3	HOP-92	Investigative	[1]
Papillary renal cell carcinoma	DCWY7OQ	ACHN	Investigative	[1]

References

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• [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: 6975).
• [3] A phase II, multicenter, open-label, 3-cohort trial evaluating the efficacy and safety of vismodegib in operable basal cell carcinoma. J Am Acad Dermatol. 2015 Jul;73(1):99-105.e1.
• [4] Dacarbazine FDA Label
• [5] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 075259.
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• [18] Mcl-1 antisense therapy chemosensitizes human melanoma in a SCID mouse xenotransplantation model. J Invest Dermatol. 2003 Jun;120(6):1081-6. doi: 10.1046/j.1523-1747.2003.12252.x.
• [19] Impairment of APE1 function enhances cellular sensitivity to clinically relevant alkylators and antimetabolites. Mol Cancer Res. 2009 Jun;7(6):897-906. doi: 10.1158/1541-7786.MCR-08-0519. Epub 2009 May 26.
• [20] Glut-1 as a therapeutic target: increased chemoresistance and HIF-1-independent link with cell turnover is revealed through COMPARE analysis and metabolomic studies. Cancer Chemother Pharmacol. 2008 Mar;61(3):377-93. doi: 10.1007/s00280-007-0480-1. Epub 2007 May 23.
• [21] Exposure of melanoma cells to dacarbazine results in enhanced tumor growth and metastasis in vivo. J Clin Oncol. 2004 Jun 1;22(11):2092-100. doi: 10.1200/JCO.2004.11.070. Epub 2004 May 3.
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