Details of the Drug Combination

General Information of Drug Combination (ID: DCKP6B0)

• Drug Combination Name: Vemurafenib + Valrubicin
• Indication: Lung adenocarcinoma; Status: Investigative [1]
• Component Drugs:
  Vemurafenib (DM62UG5): Small molecular drug
  Valrubicin (DMOYJFK): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: HOP-62
  Zero Interaction Potency (ZIP) Score: 0.3
  Bliss Independence Score: 7.08
  Loewe Additivity Score: 5.7
  LHighest Single Agent (HSA) Score: 5.74

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	[5]

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	[8]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[9]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[9]

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	[10]

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	[6]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[11]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[12]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[7]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[7]
CD70 antigen (CD70)	OTHB2AL1	CD70_HUMAN	Decreases Expression	[13]
Melanocyte protein PMEL (PMEL)	OTCDDHHM	PMEL_HUMAN	Increases Expression	[6]
Melanoma antigen recognized by T-cells 1 (MLANA)	OT1N2S2K	MAR1_HUMAN	Increases Expression	[6]

Indication(s) of Valrubicin

Disease Entry	ICD 11	Status	REF
Bladder cancer	2C94	Approved	[3]
In situ carcinoma	N.A.	Approved	[4]
Urinary bladder cancer	N.A.	Approved	[4]
Psoriasis vulgaris	EA90	Phase 2	[5]

Valrubicin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
DNA topoisomerase II (TOP2)	TT0IHXV	TOP2A_HUMAN; TOP2B_HUMAN	Inhibitor	[14]

Valrubicin Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[15]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Breast adenocarcinoma	DC357L4	MDA-MB-468	Investigative	[16]
Colon adenocarcinoma	DC9DTJU	COLO 205	Investigative	[16]
Invasive ductal carcinoma	DC1MEII	T-47D	Investigative	[16]
Invasive ductal carcinoma	DC9PF3Y	BT-549	Investigative	[16]
Invasive ductal carcinoma	DC39B6D	HS 578T	Investigative	[16]
Adenocarcinoma	DC58HRN	HT29	Investigative	[1]
Adult acute myeloid leukemia	DC38X64	HL-60(TB)	Investigative	[1]
Amelanotic melanoma	DCMQFCW	MDA-MB-435	Investigative	[1]
Amelanotic melanoma	DCHKPDP	M14	Investigative	[1]
Anaplastic large cell lymphoma	DCB5B60	SR	Investigative	[1]
Childhood T acute lymphoblastic leukemia	DCCOGH2	CCRF-CEM	Investigative	[1]
Clear cell renal cell carcinoma	DCTZ2YQ	A498	Investigative	[1]
Clear cell renal cell carcinoma	DCTU84S	TK-10	Investigative	[1]
Clear cell renal cell carcinoma	DC7I4O5	CAKI-1	Investigative	[1]
Cutaneous melanoma	DC29OJS	SK-MEL-5	Investigative	[1]
Cutaneous melanoma	DCE42W4	SK-MEL-28	Investigative	[1]
Glioblastoma	DC5QEY2	SNB-75	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCTINME	OVCAR-8	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCNUTPF	NCI\\/ADR-RES	Investigative	[1]
Malignant melanoma	DCHVQU8	LOX IMVI	Investigative	[1]
Melanoma	DC1XRDQ	MALME-3M	Investigative	[1]
Melanoma	DCN80NH	UACC-257	Investigative	[1]
Melanoma	DC8KN7T	SK-MEL-2	Investigative	[1]
Non-small cell lung carcinoma	DCB1US3	HOP-92	Investigative	[1]
Papillary renal cell carcinoma	DCR8A84	ACHN	Investigative	[1]
Plasma cell myeloma	DCSXUYR	RPMI-8226	Investigative	[1]
Pleural epithelioid mesothelioma	DCJ45H4	NCI-H226	Investigative	[1]
Renal cell carcinoma	DCSUUFW	UO-31	Investigative	[1]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125976
• [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] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [4] Valrubicin FDA Label
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013 Mar 15;19(6):1458-66.
• [10] Vemurafenib for the treatment of melanoma. Expert Opin Pharmacother. 2012 Dec;13(17):2533-43.
• [11] Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells. Elife. 2015 Aug 18;4:e04640. doi: 10.7554/eLife.04640.
• [12] 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.
• [13] 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.
• [14] Metabolic activation of N-acylanthracyclines precedes their interaction with DNA topoisomerase II. NCI Monogr. 1987;(4):111-5.
• [15] A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol Sci. 2013 Nov;136(1):216-41.
• [16] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1126165