Details of the Drug Combination

General Information of Drug Combination (ID: DCVPH61)

• Drug Combination Name: Pentamidine + Diazoxide
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Pentamidine (DMHZJCG): Small molecular drug
  Diazoxide (DML1538): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 3.61
  Bliss Independence Score: 3.61
  Loewe Additivity Score: 4.67
  LHighest Single Agent (HSA) Score: 4.67

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Pentamidine

Disease Entry	ICD 11	Status	REF
African trypanosomiasis	1F51	Approved	[2]
Fungal infection	1F29-1F2F	Approved	[3]
Pneumocystis pneumonia	CA40.20	Approved	[2]
Human immunodeficiency virus infection	1C62	Withdrawn from market	[4]

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	[8]

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	[9]

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	[10]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[10]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[10]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[10]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[10]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[11]

Pentamidine Interacts with 26 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Activity	[12]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Decreases Activity	[12]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Activity	[12]
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Decreases Activity	[12]
Nuclear protein 1 (NUPR1)	OT4FU8C0	NUPR1_HUMAN	Increases Expression	[7]
Alpha-1-antichymotrypsin (SERPINA3)	OT9BP2S0	AACT_HUMAN	Increases Expression	[7]
Serine protease hepsin (HPN)	OT7QNA61	HEPS_HUMAN	Increases Expression	[7]
Fatty acid-binding protein, liver (FABP1)	OTR34ETM	FABPL_HUMAN	Decreases Expression	[7]
Asparagine synthetase (ASNS)	OT8R922G	ASNS_HUMAN	Increases Expression	[7]
Solute carrier family 2, facilitated glucose transporter member 3 (SLC2A3)	OT2HZK5M	GTR3_HUMAN	Decreases Expression	[7]
Lanosterol synthase (LSS)	OT9W2SFH	LSS_HUMAN	Decreases Expression	[7]
Inhibin beta E chain (INHBE)	OTOI2NYG	INHBE_HUMAN	Increases Expression	[7]
Nuclear receptor subfamily 0 group B member 2 (NR0B2)	OT7UVICX	NR0B2_HUMAN	Increases Expression	[7]
Fibronectin type III domain-containing protein 4 (FNDC4)	OTOQK0WK	FNDC4_HUMAN	Increases Expression	[7]
Protein DEPP1 (DEPP1)	OTB36PHJ	DEPP1_HUMAN	Increases Expression	[7]
Nibrin (NBN)	OT73B5MD	NBN_HUMAN	Affects Localization	[13]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Decreases Expression	[14]
HLA class II histocompatibility antigen, DQ beta 1 chain (HLA-DQB1)	OTVVI3UI	DQB1_HUMAN	Affects Expression	[15]
Interferon gamma receptor 1 (IFNGR1)	OTCTQBWW	INGR1_HUMAN	Increases Expression	[16]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Affects Localization	[13]
Double-strand break repair protein MRE11 (MRE11)	OTGU8TZM	MRE11_HUMAN	Decreases Activity	[13]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[17]
Serine-protein kinase ATM (ATM)	OTQVOHLT	ATM_HUMAN	Decreases Activity	[13]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[18]
Histone acetyltransferase KAT5 (KAT5)	OTL7257A	KAT5_HUMAN	Decreases Activity	[13]
Bile acid receptor (NR1H4)	OTWZLPTB	NR1H4_HUMAN	Increases Activity	[19]

Indication(s) of Diazoxide

Disease Entry	ICD 11	Status	REF
Congenital hyperinsulinism	5A4Y	Approved	[5]
Hyperinsulinemia	5A4Y	Approved	[5]
Hypertension	BA00-BA04	Approved	[6]
Hypertensive emergency	BA03	Approved	[5]
Insulinoma	2C10.1	Approved	[5]
Malignant essential hypertension	BA00	Approved	[5]

Diazoxide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Potassium channel unspecific (KC)	TT1VOHK	NOUNIPROTAC	Modulator	[20]

Diazoxide Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Secretion	[21]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Secretion	[21]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Increases Activity	[22]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Decreases Secretion	[21]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[23]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Decreases Expression	[23]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Increases Expression	[22]
ATP-sensitive inward rectifier potassium channel 11 (KCNJ11)	OTPUUELV	KCJ11_HUMAN	Decreases Expression	[24]

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] Pentamidine FDA Label
• [3] Opportunities and challenges in antiparasitic drug discovery. Nat Rev Drug Discov. 2005 Sep;4(9):727-40.
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] Diazoxide 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: 2409).
• [7] 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.
• [8] Inhibitors of tryptase for the treatment of mast cell-mediated diseases. Curr Pharm Des. 1998 Oct;4(5):381-96.
• [9] Transport of dicationic drugs pentamidine and furamidine by human organic cation transporters. Drug Metab Dispos. 2009 Feb;37(2):424-30.
• [10] 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.
• [11] Value of preemptive CYP2C19 genotyping in allogeneic stem cell transplant patients considered for pentamidine administration. Clin Transplant. 2011 May-Jun;25(3):E271-5.
• [12] 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.
• [13] 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.
• [14] Profiling the immunotoxicity of chemicals based on in vitro evaluation by a combination of the Multi-ImmunoTox assay and the IL-8 Luc assay. Arch Toxicol. 2018 Jun;92(6):2043-2054. doi: 10.1007/s00204-018-2199-7. Epub 2018 Mar 29.
• [15] 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.
• [16] 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.
• [17] Identification of human Ether--go-go related gene modulators by three screening platforms in an academic drug-discovery setting. Assay Drug Dev Technol. 2010 Dec;8(6):727-42. doi: 10.1089/adt.2010.0331.
• [18] 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.
• [19] 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.
• [20] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [21] Antihypertensive drugs clonidine, diazoxide, hydralazine and furosemide regulate the production of cytokines by placentas and peripheral blood mononuclear cells in normal pregnancy. J Hypertens. 2006 May;24(5):915-22. doi: 10.1097/01.hjh.0000222762.84605.03.
• [22] Diazoxide-mediated preconditioning against apoptosis involves activation of cAMP-response element-binding protein (CREB) and NFkappaB. J Biol Chem. 2004 Nov 5;279(45):46748-54. doi: 10.1074/jbc.M406217200. Epub 2004 Aug 23.
• [23] Diazoxide-mediated growth inhibition in human lung cancer cells via downregulation of beta-catenin-mediated cyclin D1 transcription. Lung. 2009 Jan-Feb;187(1):61-7. doi: 10.1007/s00408-008-9127-1. Epub 2008 Dec 4.
• [24] Combined contributions of over-secreted glucagon-like peptide 1 and suppressed insulin secretion to hyperglycemia induced by gatifloxacin in rats. Toxicol Appl Pharmacol. 2013 Feb 1;266(3):375-84. doi: 10.1016/j.taap.2012.11.015. Epub 2012 Nov 28.