Details of the Drug Combination

General Information of Drug Combination (ID: DC4R0IA)

• Drug Combination Name: ZM-447439 + Mefloquine
• Indication: DD2; Status: Investigative [1]
• Component Drugs:
  ZM-447439 (DMFP8WE): Small molecular drug
  Mefloquine (DMWT905): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: DD2
  Zero Interaction Potency (ZIP) Score: 7.597
  Bliss Independence Score: 8.19
  Loewe Additivity Score: 3.573
  LHighest Single Agent (HSA) Score: 8.378

Molecular Interaction Atlas of This Drug Combination

Indication(s) of ZM-447439

Disease Entry	ICD 11	Status	REF
Discovery agent	N.A.	Investigative	[2]

ZM-447439 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Aurora kinase A (AURKA)	TTPS3C0	AURKA_HUMAN	Inhibitor	[7]

ZM-447439 Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Neurogenic locus notch homolog protein 1 (NOTCH1)	OTI1WADQ	NOTC1_HUMAN	Increases Expression	[8]
Aurora kinase B (AURKB)	OTIY4VHU	AURKB_HUMAN	Affects Localization	[9]

Indication(s) of Mefloquine

Disease Entry	ICD 11	Status	REF
Malaria	1F40-1F45	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[4]
Middle East Respiratory Syndrome (MERS)	1D64	Preclinical	[5]
Severe acute respiratory syndrome (SARS)	1D65	Preclinical	[5]
Progressive multifocal leukoencephalopathy	8A45.02	Investigative	[6]

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	[10]

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	[11]

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	[12]

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] 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: 8353).
• [3] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (NDA) 019578
• [4] 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.
• [5] Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob Agents Chemother. 2014 Aug;58(8):4885-93.
• [6] Mefloquine FDA Label
• [7] Accurate prediction of the relative potencies of members of a series of kinase inhibitors using molecular docking and MM-GBSA scoring. J Med Chem. 2006 Aug 10;49(16):4805-8.
• [8] PLK1 targets NOTCH1 during DNA damage and mitotic progression. J Biol Chem. 2019 Nov 22;294(47):17941-17950. doi: 10.1074/jbc.RA119.009881. Epub 2019 Oct 9.
• [9] DNA double-strand breaks and Aurora B mislocalization induced by exposure of early mitotic cells to H(2)O(2) appear to increase chromatin bridges and resultant cytokinesis failure. Free Radic Biol Med. 2017 Jul;108:129-145. doi: 10.1016/j.freeradbiomed.2017.03.025. Epub 2017 Mar 24.
• [10] An ultrastructural study of the effects of mefloquine on malaria parasites. Am J Trop Med Hyg. 1987 Jan;36(1):9-14.
• [11] Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther. 2004 Jan;75(1):13-33.
• [12] Effect of rifampin on plasma concentrations of mefloquine in healthy volunteers. J Pharm Pharmacol. 2000 Oct;52(10):1265-9.