Details of the Drug Combination

General Information of Drug Combination (ID: DCKMRID)

• Drug Combination Name: Trifluridine + Mechlorethamine
• Indication: Malignant melanoma; Status: Investigative [1]
• Component Drugs:
  Trifluridine (DMG2YBD): Small molecular drug
  Mechlorethamine (DM0CVXA): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: LOX IMVI
  Zero Interaction Potency (ZIP) Score: 4.56
  Bliss Independence Score: 1.83
  Loewe Additivity Score: 5.74
  LHighest Single Agent (HSA) Score: 7.07

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	[7]

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	[8]
Concentrative nucleoside transporter 1 (SLC28A1)	DT0EQPW	S28A1_HUMAN	Substrate	[9]
Equilibrative nucleoside transporter 1 (SLC29A1)	DTXD1TQ	S29A1_HUMAN	Substrate	[9]
Equilibrative nucleoside transporter 2 (SLC29A2)	DTW78DQ	S29A2_HUMAN	Substrate	[9]

Trifluridine Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Thymidine phosphorylase (TYMP)	DE4HCYL	TYPH_HUMAN	Metabolism	[10]

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	[11]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Affects Activity	[12]
Cathepsin B (CTSB)	OTP9G5QB	CATB_HUMAN	Increases Cleavage	[13]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[13]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Cleavage	[13]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Cleavage	[13]
Nuclear factor erythroid 2-related factor 2 (NFE2L2)	OT0HENJ5	NF2L2_HUMAN	Increases Activity	[14]

Indication(s) of Mechlorethamine

Disease Entry	ICD 11	Status	REF
Chronic myelogenous leukaemia	2A20.0	Approved	[4]
Lung cancer	2C25.0	Approved	[4]
Mycosis fungoides	2B01	Approved	[4]
Primary cutaneous T-cell lymphoma	N.A.	Approved	[4]
Small lymphocytic lymphoma	2A82.0	Approved	[4]
T-cell lymphoma	2A90	Approved	[5]
Hodgkin lymphoma	2B30	Phase 3	[6]
Classic Hodgkin lymphoma	N.A.	Investigative	[4]

Mechlorethamine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human Deoxyribonucleic acid (hDNA)	TTUTN1I	NOUNIPROTAC	Intercalator	[17]

Mechlorethamine Interacts with 19 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Receptor tyrosine-protein kinase erbB-2 (ERBB2)	OTOAUNCK	ERBB2_HUMAN	Decreases Expression	[18]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Decreases Activity	[19]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Increases Expression	[20]
Cyclin-dependent kinase 1 (CDK1)	OTW1SC2N	CDK1_HUMAN	Decreases Activity	[21]
Glutathione S-transferase A2 (GSTA2)	OTW7UB1H	GSTA2_HUMAN	Increases Expression	[22]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[20]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[23]
G2/mitotic-specific cyclin-B1 (CCNB1)	OT19S7E5	CCNB1_HUMAN	Decreases Activity	[21]
Transcription factor JunB (JUNB)	OTG2JXV5	JUNB_HUMAN	Increases Expression	[20]
Transcription factor JunD (JUND)	OTNKACJD	JUND_HUMAN	Increases Expression	[20]
Cyclin-A2 (CCNA2)	OTPHHYZJ	CCNA2_HUMAN	Increases Stability	[21]
Cyclin-dependent kinase 2 (CDK2)	OTB5DYYZ	CDK2_HUMAN	Increases Activity	[21]
Protein S100-P (S100P)	OTJCXNJG	S100P_HUMAN	Increases Expression	[24]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[25]
Caspase-2 (CASP2)	OTUDYSPP	CASP2_HUMAN	Increases Activity	[23]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[23]
Laminin subunit gamma-2 (LAMC2)	OTJMTM72	LAMC2_HUMAN	Decreases Expression	[26]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Increases Expression	[27]
Transient receptor potential cation channel subfamily A member 1 (TRPA1)	OTRDIR5M	TRPA1_HUMAN	Increases Response To Substance	[28]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adult acute myeloid leukemia	DC4J5ED	HL-60(TB)	Investigative	[29]
Invasive ductal carcinoma	DC23Y6S	HS 578T	Investigative	[30]

References

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• [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] Mechlorethamine FDA Label
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [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: 7218).
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• [14] 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.
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• [19] Nitrogen Mustard Alkylates and Cross-Links p53 in Human Keratinocytes. Chem Res Toxicol. 2022 Apr 18;35(4):636-650. doi: 10.1021/acs.chemrestox.1c00420. Epub 2022 Mar 21.
• [20] Nitrogen mustard prevents transport of Fra-1 into the nucleus to promote c-Fos- and FosB-dependent IL-8 induction in injured mouse epidermis. Toxicol Lett. 2020 Feb 1;319:256-263. doi: 10.1016/j.toxlet.2019.10.006. Epub 2019 Oct 19.
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• [22] Overexpression of GSTA2 protects against cell cycle arrest and apoptosis induced by the DNA inter-strand crosslinking nitrogen mustard, mechlorethamine. J Cell Biochem. 2005 May 15;95(2):339-51. doi: 10.1002/jcb.20440.
• [23] Inhibition of caspase-dependent mitochondrial permeability transition protects airway epithelial cells against mustard-induced apoptosis. Apoptosis. 2006 Sep;11(9):1545-59. doi: 10.1007/s10495-006-8764-1.
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• [29] 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.
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