Details of the Drug Combination

General Information of Drug Combination (ID: DCY7QVY)

• Drug Combination Name: Uracil mustard + Vemurafenib
• Indication: Anaplastic large cell lymphoma; Status: Investigative [1]
• Component Drugs:
  Uracil mustard (DMHL7OB): Small molecular drug
  Vemurafenib (DM62UG5): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: SR
  Zero Interaction Potency (ZIP) Score: 6.48
  Bliss Independence Score: 7.18
  Loewe Additivity Score: 2.67
  LHighest Single Agent (HSA) Score: 9.1

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Uracil mustard

Disease Entry	ICD 11	Status	REF
Acute myeloid leukaemia	2A60	Approved	[2]
Chronic myelogenous leukaemia	2A20.0	Approved	[3]
Polycythemia vera	2A20.4	Approved	[3]
Small lymphocytic lymphoma	2A82.0	Approved	[3]

Uracil mustard Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human Deoxyribonucleic acid (hDNA)	TTUTN1I	NOUNIPROTAC	Modulator	[5]

Uracil mustard Interacts with 5 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
GPI-linked NAD(P)(+)--arginine ADP-ribosyltransferase 1 (ART1)	OT7FBG5W	NAR1_HUMAN	Increases ADR	[6]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases ADR	[6]
Granulocyte-macrophage colony-stimulating factor (CSF2)	OT1M7D28	CSF2_HUMAN	Increases ADR	[6]
Poly polymerase 1 (PARP1)	OTIESHK4	PARP1_ARATH	Increases ADR	[6]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Increases ADR	[6]

Indication(s) of Vemurafenib

Disease Entry	ICD 11	Status	REF
Melanoma	2C30	Approved	[4]

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	[9]

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	[10]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[11]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[11]

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	[12]

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	[7]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[13]
Cyclin-dependent kinase 4 (CDK4)	OT7EP05T	CDK4_HUMAN	Decreases Expression	[14]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[15]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[14]
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	[16]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Decreases Expression	[14]
Sterol regulatory element-binding protein 1 (SREBF1)	OTWBRPAI	SRBP1_HUMAN	Decreases Expression	[17]
Melanocyte protein PMEL (PMEL)	OTCDDHHM	PMEL_HUMAN	Increases Expression	[7]
Melanoma-associated antigen 1 (MAGEA1)	OTXAO193	MAGA1_HUMAN	Decreases Expression	[7]
Thyroxine 5-deiodinase (DIO3)	OTNTITOT	IOD3_HUMAN	Decreases Expression	[18]
Melanoma antigen recognized by T-cells 1 (MLANA)	OT1N2S2K	MAR1_HUMAN	Increases Expression	[7]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Increases Expression	[15]
GTPase KRas (KRAS)	OT78QCN8	RASK_HUMAN	Affects Response To Substance	[19]
Serine/threonine-protein kinase B-raf (BRAF)	OT7S81XQ	BRAF_HUMAN	Increases Response To Substance	[20]
Heat shock 70 kDa protein 1A (HSPA1A)	OTKGIE76	HS71A_HUMAN	Decreases Response To Substance	[21]
GTPase NRas (NRAS)	OTVQ1DG3	RASN_HUMAN	Affects Response To Substance	[19]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adenocarcinoma	DCGJD01	HT29	Investigative	[22]

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: 7621).
• [3] Uracil mustard FDA Label
• [4] 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).
• [5] Excision of DNA adducts of nitrogen mustards by bacterial and mammalian 3-methyladenine-DNA glycosylases. Carcinogenesis. 1996 Apr;17(4):643-8.
• [6] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
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• [9] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [10] 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.
• [11] Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013 Mar 15;19(6):1458-66.
• [12] Vemurafenib for the treatment of melanoma. Expert Opin Pharmacother. 2012 Dec;13(17):2533-43.
• [13] Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells. Elife. 2015 Aug 18;4:e04640. doi: 10.7554/eLife.04640.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] 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.