Details of the Drug Combination

General Information of Drug Combination (ID: DCFIUMX)

• Drug Combination Name: Uracil mustard + Thioguanine
• Indication: Clear cell renal cell carcinoma; Status: Investigative [1]
• Component Drugs:
  Uracil mustard (DMHL7OB): Small molecular drug
  Thioguanine (DM7NKEV): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: 786-0
  Zero Interaction Potency (ZIP) Score: 3.24
  Bliss Independence Score: 6.03
  Loewe Additivity Score: 2.62
  LHighest Single Agent (HSA) Score: 7.36

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	[8]

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	[9]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases ADR	[9]
Granulocyte-macrophage colony-stimulating factor (CSF2)	OT1M7D28	CSF2_HUMAN	Increases ADR	[9]
Poly polymerase 1 (PARP1)	OTIESHK4	PARP1_ARATH	Increases ADR	[9]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Increases ADR	[9]

Indication(s) of Thioguanine

Disease Entry	ICD 11	Status	REF
Acute lymphocytic leukaemia	2B33.3	Approved	[4]
Acute myelogenous leukaemia	2A41	Approved	[5]
Acute myeloid leukaemia	2A60	Approved	[6]
Middle East Respiratory Syndrome (MERS)	1D64	Preclinical	[7]
Severe acute respiratory syndrome (SARS)	1D65	Preclinical	[7]

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	[7]
Inosine-5'-monophosphate dehydrogenase (IMPDH)	TTCAQMW	NOUNIPROTAC	Intercalator	[10]
SARS-CoV papain-like proteinase (PL-PRO)	TTRGHB2	R1AB_CVHSA (819-2740)	Inhibitor	[7]

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	[11]
Multidrug resistance-associated protein 4 (ABCC4)	DTCSGPB	MRP4_HUMAN	Substrate	[12]
Concentrative Na(+)-nucleoside cotransporter 3 (SLC28A3)	DT4YL5R	S28A3_HUMAN	Substrate	[13]

Thioguanine Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Thiopurine methyltransferase (TPMT)	DEFQ8VO	TPMT_HUMAN	Metabolism	[14]
Hypoxanthine phosphoribosyltransferase (HPRT1)	DEVXTP5	HPRT_HUMAN	Metabolism	[15]

Thioguanine Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Thiopurine S-methyltransferase (TPMT)	OTFOX70W	TPMT_HUMAN	Increases ADR	[9]
Hypoxanthine-guanine phosphoribosyltransferase (HPRT1)	OTOEEEXG	HPRT_HUMAN	Decreases Response To Substance	[16]
Thiopurine S-methyltransferase (TPMT)	OTFOX70W	TPMT_HUMAN	Increases ADR	[17]
Inosine-5'-monophosphate dehydrogenase 2 (IMPDH2)	OTPG0K7E	IMDH2_HUMAN	Increases Expression	[18]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Activity	[19]
Dystrophin (DMD)	OTD21T5J	DMD_HUMAN	Increases Splicing	[20]
Occludin (OCLN)	OTSUTVWL	OCLN_HUMAN	Decreases Activity	[21]
DNA mismatch repair protein Msh2 (MSH2)	OT10H1AB	MSH2_HUMAN	Increases Response To Substance	[22]
ATP-binding cassette sub-family C member 5 (ABCC5)	OT34G4US	MRP5_HUMAN	Decreases Response To Substance	[23]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Response To Substance	[19]
Baculoviral IAP repeat-containing protein 2 (BIRC2)	OTFXFREP	BIRC2_HUMAN	Decreases Response To Substance	[24]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adult acute myeloid leukemia	DCU0BGK	HL-60(TB)	Investigative	[1]
Anaplastic large cell lymphoma	DCJ7O5G	SR	Investigative	[1]
Astrocytoma	DC5XSIZ	SNB-19	Investigative	[1]
Glioma	DCQ1OP1	SF-295	Investigative	[1]
Papillary renal cell carcinoma	DC3OHS7	ACHN	Investigative	[1]
Carcinoma	DCMISZF	RXF 393	Investigative	[25]
Lung adenocarcinoma	DCYZHEC	EKVX	Investigative	[26]
Melanoma	DCB126I	SK-MEL-2	Investigative	[26]

References

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• [3] Uracil mustard FDA Label
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] Thioguanine FDA Label
• [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: 6845).
• [7] Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus. Antiviral Res. 2015 Mar;115:9-16.
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• [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.
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