Details of the Drug Combination

General Information of Drug Combination (ID: DCM07CO)

• Drug Combination Name: Amiloride + Pentamidine
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Amiloride (DMRTSGP): Small molecular drug
  Pentamidine (DMHZJCG): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 10.41
  Bliss Independence Score: 10.41
  Loewe Additivity Score: 24.04
  LHighest Single Agent (HSA) Score: 24.04

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 7 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Increases Expression	[11]
Receptor tyrosine-protein kinase erbB-2 (ERBB2)	OTOAUNCK	ERBB2_HUMAN	Decreases Phosphorylation	[12]
Myogenic factor 5 (MYF5)	OTTVO2S5	MYF5_HUMAN	Increases Expression	[13]
Pancreas/duodenum homeobox protein 1 (PDX1)	OTX1DKRA	PDX1_HUMAN	Decreases Uptake	[14]
Serine/threonine-protein phosphatase PP1-alpha catalytic subunit (PPP1CA)	OT7Y43A1	PP1A_HUMAN	Decreases Phosphorylation	[12]
Multidrug and toxin extrusion protein 1 (SLC47A1)	OTZX0U5Q	S47A1_HUMAN	Decreases Activity	[15]
Glutamate receptor-interacting protein 1 (GRIP1)	OT958HK1	GRIP1_HUMAN	Affects Response To Substance	[16]

Indication(s) of Pentamidine

Disease Entry	ICD 11	Status	REF
African trypanosomiasis	1F51	Approved	[4]
Fungal infection	1F29-1F2F	Approved	[5]
Pneumocystis pneumonia	CA40.20	Approved	[4]
Human immunodeficiency virus infection	1C62	Withdrawn from market	[6]

Pentamidine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Tryptase alpha/beta-1 (Tryptase)	TTM1TDX	TRYB1_HUMAN	Inhibitor	[18]

Pentamidine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[19]

Pentamidine Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[20]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[20]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[20]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[20]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[20]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[21]

Pentamidine Interacts with 16 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Activity	[22]
Nuclear protein 1 (NUPR1)	OT4FU8C0	NUPR1_HUMAN	Increases Expression	[17]
Alpha-1-antichymotrypsin (SERPINA3)	OT9BP2S0	AACT_HUMAN	Increases Expression	[17]
Solute carrier family 2, facilitated glucose transporter member 3 (SLC2A3)	OT2HZK5M	GTR3_HUMAN	Decreases Expression	[17]
Inhibin beta E chain (INHBE)	OTOI2NYG	INHBE_HUMAN	Increases Expression	[17]
Nuclear receptor subfamily 0 group B member 2 (NR0B2)	OT7UVICX	NR0B2_HUMAN	Increases Expression	[17]
Fibronectin type III domain-containing protein 4 (FNDC4)	OTOQK0WK	FNDC4_HUMAN	Increases Expression	[17]
Protein DEPP1 (DEPP1)	OTB36PHJ	DEPP1_HUMAN	Increases Expression	[17]
Nibrin (NBN)	OT73B5MD	NBN_HUMAN	Affects Localization	[23]
HLA class II histocompatibility antigen, DQ beta 1 chain (HLA-DQB1)	OTVVI3UI	DQB1_HUMAN	Affects Expression	[24]
Interferon gamma receptor 1 (IFNGR1)	OTCTQBWW	INGR1_HUMAN	Increases Expression	[25]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Affects Localization	[23]
Double-strand break repair protein MRE11 (MRE11)	OTGU8TZM	MRE11_HUMAN	Decreases Activity	[23]
Serine-protein kinase ATM (ATM)	OTQVOHLT	ATM_HUMAN	Decreases Activity	[23]
Histone acetyltransferase KAT5 (KAT5)	OTL7257A	KAT5_HUMAN	Decreases Activity	[23]
Bile acid receptor (NR1H4)	OTWZLPTB	NR1H4_HUMAN	Increases Activity	[26]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [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] Pentamidine FDA Label
• [5] Opportunities and challenges in antiparasitic drug discovery. Nat Rev Drug Discov. 2005 Sep;4(9):727-40.
• [6] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [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.
• [9] Characterization of regulatory mechanisms and states of human organic cation transporter 2. Am J Physiol Cell Physiol. 2006 Jun;290(6):C1521-31.
• [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.
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• [14] PDX-1 protein is internalized by lipid raft-dependent macropinocytosis. Cell Transplant. 2005;14(9):637-45. doi: 10.3727/000000005783982648.
• [15] 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.
• [16] 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.
• [17] A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system. Toxicol Sci. 2005 Feb;83(2):282-92.
• [18] Inhibitors of tryptase for the treatment of mast cell-mediated diseases. Curr Pharm Des. 1998 Oct;4(5):381-96.
• [19] Transport of dicationic drugs pentamidine and furamidine by human organic cation transporters. Drug Metab Dispos. 2009 Feb;37(2):424-30.
• [20] Identification of human cytochrome P(450)s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data. Eur J Clin Pharmacol. 2003 Sep;59(5-6):429-42.
• [21] Value of preemptive CYP2C19 genotyping in allogeneic stem cell transplant patients considered for pentamidine administration. Clin Transplant. 2011 May-Jun;25(3):E271-5.
• [22] Application of higher throughput screening (HTS) inhibition assays to evaluate the interaction of antiparasitic drugs with cytochrome P450s. Drug Metab Dispos. 2001 Jan;29(1):30-5.
• [23] Bisbenzamidine derivative, pentamidine represses DNA damage response through inhibition of histone H2A acetylation. Mol Cancer. 2010 Feb 9;9:34. doi: 10.1186/1476-4598-9-34.
• [24] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [25] Antileishmanial drugs cause up-regulation of interferon-gamma receptor 1, not only in the monocytes of visceral leishmaniasis cases but also in cultured THP1 cells. Ann Trop Med Parasitol. 2003 Apr;97(3):245-57. doi: 10.1179/000349803235001714.
• [26] Investigation of imatinib and other approved drugs as starting points for antidiabetic drug discovery with FXR modulating activity. Biochem Pharmacol. 2012 Jun 15;83(12):1674-81. doi: 10.1016/j.bcp.2012.02.027. Epub 2012 Mar 7.