Details of the Drug Combination

General Information of Drug Combination (ID: DCMRB5Y)

• Drug Combination Name: YM155 + Tamoxifen
• Indication: Diffuse intrinsic pontine glioma; Status: Investigative [1]
• Component Drugs:
  YM155 (DM5Q1W4): Small molecular drug
  Tamoxifen (DMLB0EZ): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: SU-DIPG-XIII
  Zero Interaction Potency (ZIP) Score: 5.342
  Bliss Independence Score: 11.565
  Loewe Additivity Score: 1.046
  LHighest Single Agent (HSA) Score: 4.319

Molecular Interaction Atlas of This Drug Combination

Indication(s) of YM155

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Phase 2	[2]
Non-hodgkin lymphoma	2B33.5	Phase 2	[2]

YM155 Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[5]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[5]

YM155 Interacts with 16 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[6]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Decreases Phosphorylation	[7]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[8]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[8]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[8]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[8]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Cleavage	[8]
POU domain, class 5, transcription factor 1 (POU5F1)	OTDHHN7O	PO5F1_HUMAN	Decreases Expression	[7]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[8]
Sequestosome-1 (SQSTM1)	OTGY5D5J	SQSTM_HUMAN	Decreases Expression	[8]
Beclin-1 (BECN1)	OT4X293M	BECN1_HUMAN	Increases Expression	[8]
ELAV-like protein 1 (ELAVL1)	OTY55PLY	ELAV1_HUMAN	Decreases Expression	[8]
Histone-lysine N-methyltransferase EHMT2 (EHMT2)	OTC4DWB6	EHMT2_HUMAN	Decreases Expression	[7]
Microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B)	OTUYHB84	MLP3B_HUMAN	Increases Lipidation	[8]
Histone-lysine N-methyltransferase EHMT1 (EHMT1)	OT6QC8GK	EHMT1_HUMAN	Decreases Expression	[7]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Response To Substance	[9]

Indication(s) of Tamoxifen

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Approved	[3]
Inflammatory breast cancer	2C62	Approved	[4]
Invasive ductal breast carcinoma	N.A.	Approved	[4]

Tamoxifen Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Estrogen receptor (ESR)	TTZAYWL	ESR1_HUMAN	Antagonist	[10]

Tamoxifen Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[11]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[12]
Multidrug resistance-associated protein 7 (ABCC10)	DTPS120	MRP7_HUMAN	Substrate	[13]

Tamoxifen Interacts with 16 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[14]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[15]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[16]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[17]
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Metabolism	[18]
Sulfotransferase 1A1 (SULT1A1)	DEYWLRK	ST1A1_HUMAN	Metabolism	[19]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[20]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[21]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[17]
Thiopurine methyltransferase (TPMT)	DEFQ8VO	TPMT_HUMAN	Metabolism	[22]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[23]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[24]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[25]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[26]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[27]
UDP-glucuronosyltransferase 1A10 (UGT1A10)	DEL5N6Y	UD110_HUMAN	Metabolism	[28]

Tamoxifen Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Coagulation factor V (F5)	OTDMZ3LT	FA5_HUMAN	Increases ADR	[29]

References

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• [2] ClinicalTrials.gov (NCT00818480) An Extension Study Administering YM155 to Subjects Previously Enrolled in Another Protocol Administering YM155. U.S. National Institutes of Health.
• [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: 1016).
• [4] Tamoxifen FDA Label
• [5] Characterization of human organic cation transporter 1 (OCT1/SLC22A1)- and OCT2 (SLC22A2)-mediated transport of 1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)- 4,9-dihydro-1H-naphtho[2,3-d]imidazolium bromide (YM155 monobromide), a novel small molecule survivin suppressant. Drug Metab Dispos. 2010 Jan;38(1):1-4.
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• [12] The phytoestrogen genistein enhances multidrug resistance in breast cancer cell lines by translational regulation of ABC transporters. Cancer Lett. 2016 Jun 28;376(1):165-72.
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• [16] Functional significance of UDP-glucuronosyltransferase variants in the metabolism of active tamoxifen metabolites. Cancer Res. 2009 Mar 1;69(5):1892-900.
• [17] Genotoxicity of tamoxifen, tamoxifen epoxide and toremifene in human lymphoblastoid cells containing human cytochrome P450s. Carcinogenesis. 1994 Jan;15(1):5-9.
• [18] Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4-hydroxy, 4'-hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen. Drug Metab Dispos. 2002 Aug;30(8):869-74.
• [19] Tamoxifen-induced adduct formation and cell stress in human endometrial glands. Drug Metab Dispos. 2010 Jan;38(1):200-7.
• [20] CYP2D6 polymorphisms and tamoxifen metabolism: clinical relevance. Curr Oncol Rep. 2010 Jan;12(1):7-15.
• [21] Polymorphisms in cytochrome P4503A5 (CYP3A5) may be associated with race and tumor characteristics, but not metabolism and side effects of tamoxifen in breast cancer patients. Cancer Lett. 2005 Jan 10;217(1):61-72.
• [22] Polymorphism of estrogen metabolism genes and cataract. Med Hypotheses. 2004;63(3):494-7.
• [23] Drug Interactions Flockhart Table
• [24] Tamoxifen inhibits cytochrome P450 2C9 activity in breast cancer patients. J Chemother. 2006 Aug;18(4):421-4.
• [25] Effect of tamoxifen on the enzymatic activity of human cytochrome CYP2B6. J Pharmacol Exp Ther. 2002 Jun;301(3):945-52.
• [26] Cytochrome P450 pharmacogenetics and cancer. Oncogene. 2006 Mar 13;25(11):1679-91.
• [27] Metabolism and transport of tamoxifen in relation to its effectiveness: new perspectives on an ongoing controversy. Future Oncol. 2014 Jan;10(1):107-22.
• [28] Glucuronidation of active tamoxifen metabolites by the human UDP glucuronosyltransferases. Drug Metab Dispos. 2007 Nov;35(11):2006-14.
• [29] Factor V Leiden mutation and thromboembolism risk in women receiving adjuvant tamoxifen for breast cancer. J Natl Cancer Inst. 2010 Jul 7;102(13):942-9. doi: 10.1093/jnci/djq211. Epub 2010 Jun 16.