Details of the Drug Combination

General Information of Drug Combination (ID: DCZ6NYQ)

• Drug Combination Name: Mebendazole + Mefloquine
• Indication: Primitive neuroectodermal tumor; Status: Investigative [1]
• Component Drugs:
  Mebendazole (DMO14SG): Small molecular drug
  Mefloquine (DMWT905): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: TC-32
  Zero Interaction Potency (ZIP) Score: 0.69
  Bliss Independence Score: 6.23
  Loewe Additivity Score: 1.08
  LHighest Single Agent (HSA) Score: 1.61

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Mebendazole

Disease Entry	ICD 11	Status	REF
Ascariasis	1F62	Approved	[2]
Enterobiasis	1F65	Approved	[2]
Helminth infection	1F90.0	Approved	[2]
Trichuris trichiura infection	1F6G	Approved	[2]
Worm infection	1F90.Z	Approved	[3]

Mebendazole Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Tubulin beta (TUBB)	TTYFKSZ	NOUNIPROTAC	Binder	[9]

Mebendazole Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[10]

Mebendazole Interacts with 23 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Increases Expression	[11]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Increases Expression	[12]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[13]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[11]
Protein S100-A8 (S100A8)	OTVMOB3F	S10A8_HUMAN	Increases Expression	[14]
Protein S100-A9 (S100A9)	OTOARHCS	S10A9_HUMAN	Increases Expression	[14]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Expression	[15]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Expression	[11]
Interleukin-6 receptor subunit alpha (IL6R)	OTCQL07Z	IL6RA_HUMAN	Increases Expression	[8]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[16]
Solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1)	OTA675TJ	GTR1_HUMAN	Decreases Expression	[17]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[8]
Hexokinase-1 (HK1)	OTMPHE8O	HXK1_HUMAN	Decreases Expression	[17]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[16]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[16]
Mitogen-activated protein kinase 8 (MAPK8)	OTEREYS5	MK08_HUMAN	Increases Phosphorylation	[16]
Mitogen-activated protein kinase 9 (MAPK9)	OTCEVJ9E	MK09_HUMAN	Increases Phosphorylation	[16]
Neurogenic locus notch homolog protein 1 (NOTCH1)	OTI1WADQ	NOTC1_HUMAN	Decreases Expression	[18]
Transcription factor HES-1 (HES1)	OT8P19W2	HES1_HUMAN	Decreases Expression	[18]
PTB-containing, cubilin and LRP1-interacting protein (PID1)	OT5YJ7FI	PCLI1_HUMAN	Increases Expression	[11]
Rho guanine nucleotide exchange factor 2 (ARHGEF2)	OTBQTFRT	ARHG2_HUMAN	Decreases Expression	[19]
Multidrug and toxin extrusion protein 1 (SLC47A1)	OTZX0U5Q	S47A1_HUMAN	Decreases Expression	[15]
NACHT, LRR and PYD domains-containing protein 3 (NLRP3)	OTZM6MHU	NLRP3_HUMAN	Increases Expression	[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	[20]

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	[21]

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	[22]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Chronic myelogenous leukemia	DCLDN5P	KBM-7	Investigative	[1]
Diffuse intrinsic pontine glioma	DCW09SC	SU-DIPG-XIII	Investigative	[1]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [2] Mebendazole FDA Label
• [3] Emerging drugs for irritable bowel syndrome. Expert Opin Emerg Drugs. 2006 May;11(2):293-313.
• [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] Cell-based and cytokine-directed chemical screen to identify potential anti-multiple myeloma agents. Leuk Res. 2010 Jul;34(7):917-24. doi: 10.1016/j.leukres.2009.12.002. Epub 2010 Feb 8.
• [9] Flubendazole interferes with a wide spectrum of cell homeostatic mechanisms in Echinococcus granulosus protoscoleces. Parasitol Int. 2009 Sep;58(3):270-7.
• [10] Alveolar echinococcosis of the liver in an adult with human immunodeficiency virus type-1 infection. Infection. 2004 Oct;32(5):299-302.
• [11] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
• [12] 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.
• [13] Mebendazole induces apoptosis via C-MYC inactivation in malignant ascites cell line (AGP01). Toxicol In Vitro. 2019 Oct;60:305-312. doi: 10.1016/j.tiv.2019.06.010. Epub 2019 Jun 14.
• [14] Development of a cell-based assay system considering drug metabolism and immune- and inflammatory-related factors for the risk assessment of drug-induced liver injury. Toxicol Lett. 2014 Jul 3;228(1):13-24. doi: 10.1016/j.toxlet.2014.04.005. Epub 2014 Apr 15.
• [15] Mebendazole, an antiparasitic drug, inhibits drug transporters expression in preclinical model of gastric peritoneal carcinomatosis. Toxicol In Vitro. 2017 Sep;43:87-91. doi: 10.1016/j.tiv.2017.06.007. Epub 2017 Jun 9.
• [16] Stimulation of pro-inflammatory responses by mebendazole in human monocytic THP-1 cells through an ERK signaling pathway. Arch Toxicol. 2011 Mar;85(3):199-207. doi: 10.1007/s00204-010-0584-y. Epub 2010 Sep 17.
• [17] Mebendazole targets essential proteins in glucose metabolism leading gastric cancer cells to death. Toxicol Appl Pharmacol. 2023 Sep 15;475:116630. doi: 10.1016/j.taap.2023.116630. Epub 2023 Jul 18.
• [18] Mebendazole is a potent inhibitor to chemoresistant T cell acute lymphoblastic leukemia cells. Toxicol Appl Pharmacol. 2020 Jun 1;396:115001. doi: 10.1016/j.taap.2020.115001. Epub 2020 Apr 8.
• [19] Flubendazole and mebendazole impair migration and epithelial to mesenchymal transition in oral cell lines. Chem Biol Interact. 2018 Sep 25;293:124-132. doi: 10.1016/j.cbi.2018.07.026. Epub 2018 Jul 31.
• [20] An ultrastructural study of the effects of mefloquine on malaria parasites. Am J Trop Med Hyg. 1987 Jan;36(1):9-14.
• [21] Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther. 2004 Jan;75(1):13-33.
• [22] Effect of rifampin on plasma concentrations of mefloquine in healthy volunteers. J Pharm Pharmacol. 2000 Oct;52(10):1265-9.