Details of the Drug Combination

General Information of Drug Combination (ID: DCZGXXI)

• Drug Combination Name: YM155 + CYTISINE
• Indication: Diffuse intrinsic pontine glioma; Status: Investigative [1]
• Component Drugs:
  YM155 (DM5Q1W4): Small molecular drug
  CYTISINE (DMUF0BJ): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: SU-DIPG-XIII
  Zero Interaction Potency (ZIP) Score: 3.548
  Bliss Independence Score: 3.705
  Loewe Additivity Score: 0.974
  LHighest Single Agent (HSA) Score: 0.959

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	[4]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[4]

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]

Indication(s) of CYTISINE

Disease Entry	ICD 11	Status	REF
Tobacco dependence	6C4A.2	Phase 3	[3]

CYTISINE Interacts with 6 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Neuronal acetylcholine receptor alpha-7 (CHRNA7)	TTLA931	ACHA7_HUMAN	Inhibitor	[9]
Neuronal acetylcholine receptor alpha-2 (CHRNA2)	TTF4E0J	ACHA2_HUMAN	Inhibitor	[10]
Neuronal acetylcholine receptor alpha-4 (CHRNA4)	TT4H1MQ	ACHA4_HUMAN	Inhibitor	[11]
Neuronal acetylcholine receptor beta-4 (CHRNB4)	TTTVAFQ	ACHB4_HUMAN	Inhibitor	[12]
Nicotinic acetylcholine receptor (nAChR)	TTJSZTB	NOUNIPROTAC	Antagonist	[3]
Neuronal acetylcholine receptor beta-2 (CHRNB2)	TT5KPZR	ACHB2_HUMAN	Inhibitor	[11]

CYTISINE Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Neuronal acetylcholine receptor subunit alpha-4 (CHRNA4)	OT1H0ZXC	ACHA4_HUMAN	Affects Binding	[13]
Neuronal acetylcholine receptor subunit beta-2 (CHRNB2)	OTNAT2M5	ACHB2_HUMAN	Affects Binding	[13]

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] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [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] 3,5-Bicyclic aryl piperidines: a novel class of alpha4beta2 neuronal nicotinic receptor partial agonists for smoking cessation. Bioorg Med Chem Lett. 2005 Nov 15;15(22):4889-97.
• [10] Synthesis and pharmacological evaluation of novel 9- and 10-substituted cytisine derivatives. Nicotinic ligands of enhanced subtype selectivity. J Med Chem. 2006 May 4;49(9):2673-6.
• [11] Epibatidine isomers and analogues: structure-activity relationships. Bioorg Med Chem Lett. 2006 Nov 1;16(21):5493-7.
• [12] Deconstructing cytisine: The syntheses of (+/-)-cyfusine and (+/-)-cyclopropylcyfusine, fused ring analogs of cytisine. Bioorg Med Chem Lett. 2008 Apr 1;18(7):2316-9.
• [13] ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine]: I. A potent and selective cholinergic channel modulator with neuroprotective properties. J Pharmacol Exp Ther. 1997 Oct;283(1):235-46.