Details of the Drug Combination

General Information of Drug Combination (ID: DC1I0MX)

• Drug Combination Name: Trifluridine + Uracil mustard
• Indication: Malignant melanoma; Status: Investigative [1]
• Component Drugs:
  Trifluridine (DMG2YBD): Small molecular drug
  Uracil mustard (DMHL7OB): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: LOX IMVI
  Zero Interaction Potency (ZIP) Score: 3.37
  Bliss Independence Score: 0.45
  Loewe Additivity Score: 0.08
  LHighest Single Agent (HSA) Score: 4.34

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Trifluridine

Disease Entry	ICD 11	Status	REF
Herpetic keratitis	1F00.10	Approved	[2]
Virus infection	1A24-1D9Z	Approved	[3]
Colon cancer	2B90.Z	Investigative	[2]

Trifluridine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Candida Thymidylate synthase (Candi TMP1)	TTU6BFZ	TYSY_CANAL	Inhibitor	[6]

Trifluridine Interacts with 4 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic anion transporter 1 (SLC22A6)	DTQ23VB	S22A6_HUMAN	Substrate	[7]
Concentrative nucleoside transporter 1 (SLC28A1)	DT0EQPW	S28A1_HUMAN	Substrate	[8]
Equilibrative nucleoside transporter 1 (SLC29A1)	DTXD1TQ	S29A1_HUMAN	Substrate	[8]
Equilibrative nucleoside transporter 2 (SLC29A2)	DTW78DQ	S29A2_HUMAN	Substrate	[8]

Trifluridine Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Thymidine phosphorylase (TYMP)	DE4HCYL	TYPH_HUMAN	Metabolism	[9]

Trifluridine Interacts with 7 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[10]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Affects Activity	[11]
Cathepsin B (CTSB)	OTP9G5QB	CATB_HUMAN	Increases Cleavage	[12]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[12]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Cleavage	[12]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Cleavage	[12]
Nuclear factor erythroid 2-related factor 2 (NFE2L2)	OT0HENJ5	NF2L2_HUMAN	Increases Activity	[13]

Indication(s) of Uracil mustard

Disease Entry	ICD 11	Status	REF
Acute myeloid leukaemia	2A60	Approved	[4]
Chronic myelogenous leukaemia	2A20.0	Approved	[5]
Polycythemia vera	2A20.4	Approved	[5]
Small lymphocytic lymphoma	2A82.0	Approved	[5]

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	[14]

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	[15]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases ADR	[15]
Granulocyte-macrophage colony-stimulating factor (CSF2)	OT1M7D28	CSF2_HUMAN	Increases ADR	[15]
Poly polymerase 1 (PARP1)	OTIESHK4	PARP1_ARATH	Increases ADR	[15]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Increases ADR	[15]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adult acute myeloid leukemia	DC39HU4	HL-60(TB)	Investigative	[16]
Anaplastic large cell lymphoma	DCNHSY6	SR	Investigative	[16]
Childhood T acute lymphoblastic leukemia	DCADJ6I	CCRF-CEM	Investigative	[16]
Glioma	DCKJWN7	SF-295	Investigative	[16]
Colon carcinoma	DCM7XQ4	KM12	Investigative	[17]
High grade ovarian serous adenocarcinoma	DCT7NR5	OVCAR-5	Investigative	[1]

References

• [1] 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.
• [2] Trifluridine FDA Label
• [3] 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: 8697).
• [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: 7621).
• [5] Uracil mustard FDA Label
• [6] Trifluorothymidine induces cell death independently of p53. Nucleosides Nucleotides Nucleic Acids. 2008 Jun;27(6):699-703.
• [7] Rat multispecific organic anion transporter 1 (rOAT1) transports zidovudine, acyclovir, and other antiviral nucleoside analogs. J Pharmacol Exp Ther. 2000 Sep;294(3):844-9.
• [8] Lonsurf, INN-trifluridine/tipiracil.
• [9] Phase I clinical study of three times a day oral administration of TAS-102 in patients with solid tumors. Cancer Invest. 2008 Oct;26(8):794-9.
• [10] Screening of a chemical library reveals novel PXR-activating pharmacologic compounds. Toxicol Lett. 2015 Jan 5;232(1):193-202. doi: 10.1016/j.toxlet.2014.10.009. Epub 2014 Oct 16.
• [11] Identification of environmental chemicals that activate p53 signaling after in vitro metabolic activation. Arch Toxicol. 2022 Jul;96(7):1975-1987. doi: 10.1007/s00204-022-03291-5. Epub 2022 Apr 18.
• [12] Differential activation of cell death and autophagy results in an increased cytotoxic potential for trifluorothymidine compared to 5-fluorouracil in colon cancer cells. Int J Cancer. 2010 May 15;126(10):2457-68. doi: 10.1002/ijc.24943.
• [13] Identification of Compounds That Inhibit Estrogen-Related Receptor Alpha Signaling Using High-Throughput Screening Assays. Molecules. 2019 Feb 27;24(5):841. doi: 10.3390/molecules24050841.
• [14] Excision of DNA adducts of nitrogen mustards by bacterial and mammalian 3-methyladenine-DNA glycosylases. Carcinogenesis. 1996 Apr;17(4):643-8.
• [15] 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.
• [16] Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
• [17] Biologically active neutrophil chemokine pattern in tonsillitis.Clin Exp Immunol. 2004 Mar;135(3):511-8. doi: 10.1111/j.1365-2249.2003.02390.x.