Details of the Drug Combination

General Information of Drug Combination (ID: DC1BWT9)

• Drug Combination Name: ABIRATERONE + Trifluridine
• Indication: Colon carcinoma; Status: Investigative [1]
• Component Drugs:
  ABIRATERONE (DM8V75C): Small molecular drug
  Trifluridine (DMG2YBD): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KM12
  Zero Interaction Potency (ZIP) Score: 7.35
  Bliss Independence Score: 14.64
  Loewe Additivity Score: 13.35
  LHighest Single Agent (HSA) Score: 14.92

Molecular Interaction Atlas of This Drug Combination

Indication(s) of ABIRATERONE

Disease Entry	ICD 11	Status	REF
Prostate cancer	2C82.0	Approved	[2]

ABIRATERONE Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Steroid 17-alpha-monooxygenase (S17AH)	TTRA5BZ	CP17A_HUMAN	Modulator	[5]

ABIRATERONE Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1)	OTZKVLVJ	CP17A_HUMAN	Decreases Activity	[6]
Tissue factor (F3)	OT3MSU3B	TF_HUMAN	Increases Expression	[7]
Membrane cofactor protein (CD46)	OTQ8NWJD	MCP_HUMAN	Increases Expression	[8]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Decreases Response To Substance	[9]

Indication(s) of Trifluridine

Disease Entry	ICD 11	Status	REF
Herpetic keratitis	1F00.10	Approved	[3]
Virus infection	1A24-1D9Z	Approved	[4]
Colon cancer	2B90.Z	Investigative	[3]

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	[10]

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	[11]
Concentrative nucleoside transporter 1 (SLC28A1)	DT0EQPW	S28A1_HUMAN	Substrate	[12]
Equilibrative nucleoside transporter 1 (SLC29A1)	DTXD1TQ	S29A1_HUMAN	Substrate	[12]
Equilibrative nucleoside transporter 2 (SLC29A2)	DTW78DQ	S29A2_HUMAN	Substrate	[12]

Trifluridine Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Thymidine phosphorylase (TYMP)	DE4HCYL	TYPH_HUMAN	Metabolism	[13]

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	[14]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Affects Activity	[15]
Cathepsin B (CTSB)	OTP9G5QB	CATB_HUMAN	Increases Cleavage	[16]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[16]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Cleavage	[16]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Cleavage	[16]
Nuclear factor erythroid 2-related factor 2 (NFE2L2)	OT0HENJ5	NF2L2_HUMAN	Increases Activity	[17]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adult T acute lymphoblastic leukemia	DCVMKL1	MOLT-4	Investigative	[18]
Astrocytoma	DC780IS	SNB-19	Investigative	[18]
Clear cell renal cell carcinoma	DCNV2GV	TK-10	Investigative	[18]
Plasma cell myeloma	DCGD64K	RPMI-8226	Investigative	[18]
Renal cell carcinoma	DCISU6Y	SN12C	Investigative	[18]
Breast adenocarcinoma	DC15MK8	MDA-MB-468	Investigative	[1]
Adenocarcinoma	DC3H05B	SW-620	Investigative	[19]
Cutaneous melanoma	DCJSJW1	SK-MEL-28	Investigative	[19]
Lung adenocarcinoma	DCADM2T	HOP-62	Investigative	[19]
Lung adenocarcinoma	DCQVJIF	NCI-H522	Investigative	[19]

References

• [1] 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.
• [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: 6745).
• [3] Trifluridine 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: 8697).
• [5] 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
• [6] A fission yeast-based test system for the determination of IC50 values of anti-prostate tumor drugs acting on CYP21. J Enzyme Inhib Med Chem. 2006 Oct;21(5):547-56.
• [7] Elucidating mechanisms of toxicity using phenotypic data from primary human cell systems--a chemical biology approach for thrombosis-related side effects. Int J Mol Sci. 2015 Jan 5;16(1):1008-29. doi: 10.3390/ijms16011008.
• [8] Targeting CD46 for both adenocarcinoma and neuroendocrine prostate cancer. JCI Insight. 2018 Sep 6;3(17):e121497. doi: 10.1172/jci.insight.121497. eCollection 2018 Sep 6.
• [9] Targeting chromatin binding regulation of constitutively active AR variants to overcome prostate cancer resistance to endocrine-based therapies. Nucleic Acids Res. 2015 Jul 13;43(12):5880-97. doi: 10.1093/nar/gkv262. Epub 2015 Apr 23.
• [10] Trifluorothymidine induces cell death independently of p53. Nucleosides Nucleotides Nucleic Acids. 2008 Jun;27(6):699-703.
• [11] 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.
• [12] Lonsurf, INN-trifluridine/tipiracil.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.