Details of the Drug Combination

General Information of Drug Combination (ID: DCLYWF4)

• Drug Combination Name: Hydralazine + Mefloquine
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Hydralazine (DMU8JGH): Small molecular drug
  Mefloquine (DMWT905): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 5
  Bliss Independence Score: 5
  Loewe Additivity Score: 5.95
  LHighest Single Agent (HSA) Score: 5.95

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Hydralazine

Disease Entry	ICD 11	Status	REF
Chronic heart failure	BD1Z	Approved	[2]
Hypertension	BA00-BA04	Approved	[3]
Malignant essential hypertension	BA00	Approved	[2]

Hydralazine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Membrane copper amine oxidase (AOC3)	TT7HC21	AOC3_HUMAN	Modulator	[8]

Hydralazine Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
RNA cytidine acetyltransferase (hALP)	DEZV4AP	NAT10_HUMAN	Metabolism	[9]
N-acetyltransferase 1 (NAT1)	DE7OAB3	ARY1_HUMAN	Metabolism	[10]
N-acetyltransferase 2 (NAT2)	DER7TA0	ARY2_HUMAN	Metabolism	[10]

Hydralazine Interacts with 16 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Arylamine N-acetyltransferase 2 (NAT2)	OTBPDQOY	ARY2_HUMAN	Increases Acetylation	[11]
Estrogen receptor (ESR1)	OTKLU61J	ESR1_HUMAN	Increases Expression	[12]
Glutathione S-transferase P (GSTP1)	OTLP0A0Y	GSTP1_HUMAN	Increases Expression	[12]
Retinoic acid receptor beta (RARB)	OT367U3E	RARB_HUMAN	Decreases Methylation	[12]
Methylated-DNA--protein-cysteine methyltransferase (MGMT)	OT40A9WH	MGMT_HUMAN	Increases Expression	[12]
Adenomatous polyposis coli protein (APC)	OTKV0TIK	APC_HUMAN	Decreases Methylation	[12]
Cyclin-dependent kinase inhibitor 2A (CDKN2A)	OTN0ZWAE	CDN2A_HUMAN	Decreases Methylation	[12]
Bis(5'-adenosyl)-triphosphatase (FHIT)	OTGWBSLA	FHIT_HUMAN	Increases Expression	[12]
Death-associated protein kinase 1 (DAPK1)	OTNCNUCO	DAPK1_HUMAN	Increases Expression	[12]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Activity	[13]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Secretion	[14]
Collagen alpha-1(I) chain (COL1A1)	OTI31178	CO1A1_HUMAN	Decreases Expression	[15]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[16]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Activity	[17]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Secretion	[14]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Increases Secretion	[14]

Indication(s) of Mefloquine

Disease Entry	ICD 11	Status	REF
Malaria	1F40-1F45	Approved	[4]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[5]
Middle East Respiratory Syndrome (MERS)	1D64	Preclinical	[6]
Severe acute respiratory syndrome (SARS)	1D65	Preclinical	[6]
Progressive multifocal leukoencephalopathy	8A45.02	Investigative	[7]

Mefloquine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Plasmodium 80S ribosome (Malaria 80S)	TTT28H3	NOUNIPROTAC	Binder	[18]

Mefloquine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[19]

Mefloquine Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[20]

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] Hydralazine FDA Label
• [3] 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: 7326).
• [4] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (NDA) 019578
• [5] ClinicalTrials.gov (NCT04347031) An Open Randomized Study of the Effectiveness of Mefloquine for the Treatment of Patients With COVID19. U.S. National Institutes of Health.
• [6] Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob Agents Chemother. 2014 Aug;58(8):4885-93.
• [7] Mefloquine FDA Label
• [8] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [9] Prizidilol, an antihypertensive with precapillary vasodilator and beta-adrenoceptor blocking actions, in primary hypertension. Clin Pharmacol Ther. 1981 May;29(5):588-93.
• [10] N-acetyltransferase 2 genotype-dependent N-acetylation of hydralazine in human hepatocytes. Drug Metab Dispos. 2017 Dec;45(12):1276-1281.
• [11] Eukaryotic arylamine N-acetyltransferase. Investigation of substrate specificity by high-throughput screening. Biochem Pharmacol. 2005 Jan 15;69(2):347-59. doi: 10.1016/j.bcp.2004.09.014. Epub 2004 Nov 24.
• [12] A phase I study of hydralazine to demethylate and reactivate the expression of tumor suppressor genes. BMC Cancer. 2005 Apr 29;5:44.
• [13] Sympathetic activity in idiopathic dilated cardiomyopathy. Influence of captopril and hydralazine. Cardiovasc Drugs Ther. 1987 Aug;1(2):177-81. doi: 10.1007/BF02125471.
• [14] 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.
• [15] Hydralazine inhibits human peritoneal mesothelial cell proliferation and collagen synthesis. Nephrol Dial Transplant. 1996 Nov;11(11):2276-81. doi: 10.1093/oxfordjournals.ndt.a027148.
• [16] Albumin Protects Lung Cells against Acrolein Cytotoxicity and Acrolein-Adducted Albumin Increases Heme Oxygenase 1 Transcripts. Chem Res Toxicol. 2020 Jul 20;33(7):1969-1979. doi: 10.1021/acs.chemrestox.0c00146. Epub 2020 Jun 29.
• [17] High-throughput measurement of the Tp53 response to anticancer drugs and random compounds using a stably integrated Tp53-responsive luciferase reporter. Carcinogenesis. 2002 Jun;23(6):949-57. doi: 10.1093/carcin/23.6.949.
• [18] An ultrastructural study of the effects of mefloquine on malaria parasites. Am J Trop Med Hyg. 1987 Jan;36(1):9-14.
• [19] Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther. 2004 Jan;75(1):13-33.
• [20] Effect of rifampin on plasma concentrations of mefloquine in healthy volunteers. J Pharm Pharmacol. 2000 Oct;52(10):1265-9.