Details of the Drug Combination

General Information of Drug Combination (ID: DC7NR2G)

• Drug Combination Name: Amiloride + Moricizine
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Amiloride (DMRTSGP): Small molecular drug
  Moricizine (DMOMBJW): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 10.52
  Bliss Independence Score: 10.52
  Loewe Additivity Score: 26.06
  LHighest Single Agent (HSA) Score: 26.08

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Amiloride

Disease Entry	ICD 11	Status	REF
Congestive heart failure	BD10	Approved	[2]
Edema	MG29	Approved	[3]

Amiloride Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Acid-sensing ion channel 1 (ASIC1)	TTRJYB6	ASIC1_HUMAN	Modulator	[8]

Amiloride 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	[9]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[10]

Amiloride Interacts with 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Diamine oxidase (AOC1)	OTRC220K	AOC1_HUMAN	Decreases Activity	[11]
3-phosphoinositide-dependent protein kinase 1 (PDPK1)	OTT09ZVP	PDPK1_HUMAN	Decreases Phosphorylation	[12]
Dysferlin (DYSF)	OTNSKJU0	DYSF_HUMAN	Decreases Expression	[13]
Urokinase-type plasminogen activator (PLAU)	OTX0QGKK	UROK_HUMAN	Decreases Activity	[14]
Angiotensinogen (AGT)	OTBZLYR3	ANGT_HUMAN	Increases Expression	[15]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Increases Expression	[16]
Receptor tyrosine-protein kinase erbB-2 (ERBB2)	OTOAUNCK	ERBB2_HUMAN	Decreases Phosphorylation	[12]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[17]
Myogenic factor 5 (MYF5)	OTTVO2S5	MYF5_HUMAN	Increases Expression	[13]
G2/mitotic-specific cyclin-B1 (CCNB1)	OT19S7E5	CCNB1_HUMAN	Decreases Expression	[18]
Pancreas/duodenum homeobox protein 1 (PDX1)	OTX1DKRA	PDX1_HUMAN	Decreases Uptake	[19]
Serine/threonine-protein phosphatase PP1-alpha catalytic subunit (PPP1CA)	OT7Y43A1	PP1A_HUMAN	Decreases Phosphorylation	[12]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[17]
Multidrug and toxin extrusion protein 1 (SLC47A1)	OTZX0U5Q	S47A1_HUMAN	Decreases Activity	[20]
Glutamate receptor-interacting protein 1 (GRIP1)	OT958HK1	GRIP1_HUMAN	Affects Response To Substance	[21]

Indication(s) of Moricizine

Disease Entry	ICD 11	Status	REF
Arrhythmia	BC9Z	Approved	[4]
Long QT syndrome	BC65.0	Approved	[5]
Heart arrhythmia	BC65	Withdrawn from market	[6]

Moricizine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Voltage-gated sodium channel alpha Nav1.5 (SCN5A)	TTZOVE0	SCN5A_HUMAN	Blocker	[22]

Moricizine Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[23]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Increases Expression	[23]

References

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• [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: 2421).
• [3] Amiloride FDA Label
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] Moricizine FDA Label
• [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: 7244).
• [7] Reduction of intracellular pH inhibits the expression of VEGF in K562 cells after targeted inhibition of the Na+/H+ exchanger. Leuk Res. 2007 Apr;31(4):507-14. doi: 10.1016/j.leukres.2006.06.015. Epub 2006 Aug 1.
• [8] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
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• [10] Identification of novel substrates and structure-activity relationship of cellular uptake mediated by human organic cation transporters 1 and 2. J Med Chem. 2013 Sep 26;56(18):7232-42.
• [11] Diamine oxidase is the amiloride-binding protein and is inhibited by amiloride analogues. J Biol Chem. 1994 Apr 1;269(13):9921-5.
• [12] Role of HER-2/neu signaling in sensitivity to tumor necrosis factor-related apoptosis-inducing ligand: enhancement of TRAIL-mediated apoptosis by amiloride. J Cell Biochem. 2005 Oct 1;96(2):376-89. doi: 10.1002/jcb.20512.
• [13] In vivo and in vitro dysferlin expression in human muscle satellite cells. J Neuropathol Exp Neurol. 2004 Oct;63(10):1104-13. doi: 10.1093/jnen/63.10.1104.
• [14] Amplification of urokinase gene in prostate cancer. Cancer Res. 2001 Jul 15;61(14):5340-4.
• [15] Amiloride, spironolactone, and potassium chloride in thiazide-treated hypertensive patients. Clin Pharmacol Ther. 1980 Apr;27(4):533-43. doi: 10.1038/clpt.1980.75.
• [16] Selection of drugs to test the specificity of the Tg.AC assay by screening for induction of the gadd153 promoter in vitro. Toxicol Sci. 2003 Aug;74(2):260-70. doi: 10.1093/toxsci/kfg113. Epub 2003 May 2.
• [17] Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury. J Toxicol Sci. 2021;46(4):167-176. doi: 10.2131/jts.46.167.
• [18] Reduction in the radiation-induced late S phase and G2 blocks in HL-60 cell populations by amiloride, an efficient inhibitor of the Na+/H+ transporter. Cancer Res. 1998 Feb 1;58(3):413-20.
• [19] PDX-1 protein is internalized by lipid raft-dependent macropinocytosis. Cell Transplant. 2005;14(9):637-45. doi: 10.3727/000000005783982648.
• [20] Molecular identification and functional characterization of rat multidrug and toxin extrusion type transporter 1 as an organic cation/H+ antiporter in the kidney. Drug Metab Dispos. 2006 Nov;34(11):1868-74. doi: 10.1124/dmd.106.010876. Epub 2006 Aug 23.
• [21] Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study. Environ Health Perspect. 2015 May;123(5):458-66. doi: 10.1289/ehp.1408775. Epub 2015 Jan 13.
• [22] From first class to third class: recent upheaval in antiarrhythmic therapy--lessons from clinical trials. Am J Cardiol. 1996 Aug 29;78(4A):28-33.
• [23] Comparison of immortalized Fa2N-4 cells and human hepatocytes as in vitro models for cytochrome P450 induction. Drug Metab Dispos. 2008 Jun;36(6):1046-55.