Details of the Drug Combination

General Information of Drug Combination (ID: DC5GUE9)

Drug Combination Name

YM155 LY335979

Indication

Disease Entry	Status	REF
Human papillomavirus-related cervical adenocarcinoma	Investigative	[1]

Component Drugs

YM155 DM5Q1W4

LY335979 DM2KITF

Small molecular drug

2D MOL

3D MOL

High-throughput Screening Result

Testing Cell Line: KB-ChR-8-5-11

Zero Interaction Potency (ZIP) Score: 45.516

Bliss Independence Score: 45.261

Loewe Additivity Score: 13.766

LHighest Single Agent (HSA) Score: 22.131

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)

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	[4]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[4]
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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	[5]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Decreases Phosphorylation	[6]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[7]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[7]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[7]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[7]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Cleavage	[7]
POU domain, class 5, transcription factor 1 (POU5F1)	OTDHHN7O	PO5F1_HUMAN	Decreases Expression	[6]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[7]
Sequestosome-1 (SQSTM1)	OTGY5D5J	SQSTM_HUMAN	Decreases Expression	[7]
Beclin-1 (BECN1)	OT4X293M	BECN1_HUMAN	Increases Expression	[7]
ELAV-like protein 1 (ELAVL1)	OTY55PLY	ELAV1_HUMAN	Decreases Expression	[7]
Histone-lysine N-methyltransferase EHMT2 (EHMT2)	OTC4DWB6	EHMT2_HUMAN	Decreases Expression	[6]
Microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B)	OTUYHB84	MLP3B_HUMAN	Increases Lipidation	[7]
Histone-lysine N-methyltransferase EHMT1 (EHMT1)	OT6QC8GK	EHMT1_HUMAN	Decreases Expression	[6]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Response To Substance	[8]
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⏷ Show the Full List of 16 DOT(s)

Indication(s) of LY335979

Disease Entry	ICD 11	Status	REF
Acute myeloid leukaemia	2A60	Discontinued in Phase 3	[3]

LY335979 Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Multidrug resistance protein 1 (ABCB1)	TT3OT40	MDR1_HUMAN	Modulator	[9]
Multidrug resistance protein 3 (ABCB4)	TTJUXV6	MDR3_HUMAN	Modulator	[9]
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LY335979 Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Activity	[10]
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References

1	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.
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	Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005159)
4	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.
5	Inhibition of pluripotent stem cell-derived teratoma formation by small molecules. Proc Natl Acad Sci U S A. 2013 Aug 27;110(35):E3281-90. doi: 10.1073/pnas.1303669110. Epub 2013 Aug 5.
6	YM155 as an inhibitor of cancer stemness simultaneously inhibits autophosphorylation of epidermal growth factor receptor and G9a-mediated stemness in lung cancer cells. PLoS One. 2017 Aug 7;12(8):e0182149. doi: 10.1371/journal.pone.0182149. eCollection 2017.
7	Autophagic HuR mRNA degradation induces survivin and MCL1 downregulation in YM155-treated human leukemia cells. Toxicol Appl Pharmacol. 2020 Jan 15;387:114857. doi: 10.1016/j.taap.2019.114857. Epub 2019 Dec 16.
8	The SMAC mimetic LCL161 is a direct ABCB1/MDR1-ATPase activity modulator and BIRC5/Survivin expression down-regulator in cancer cells. Toxicol Appl Pharmacol. 2020 Aug 15;401:115080. doi: 10.1016/j.taap.2020.115080. Epub 2020 Jun 1.
9	A Phase I trial of a potent P-glycoprotein inhibitor, zosuquidar trihydrochloride (LY335979), administered intravenously in combination with doxoru... Clin Cancer Res. 2004 May 15;10(10):3265-72.
10	Clinical disposition, metabolism and in vitro drug-drug interaction properties of omadacycline. Xenobiotica. 2017 Aug;47(8):682-696. doi: 10.1080/00498254.2016.1213465. Epub 2016 Aug 8.