Details of the Drug Combination

General Information of Drug Combination (ID: DC4OXL1)

• Drug Combination Name: Mefloquine + KN-62
• Indication: Hepatoblastoma; Status: Investigative [1]
• Component Drugs:
  Mefloquine (DMWT905): Small molecular drug
  KN-62 (DMLZ89P): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: HB3
  Zero Interaction Potency (ZIP) Score: 11.974
  Bliss Independence Score: 13.283
  Loewe Additivity Score: 4.185
  LHighest Single Agent (HSA) Score: 8.259

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Mefloquine

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

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	[7]

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	[8]

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	[9]

Indication(s) of KN-62

Disease Entry	ICD 11	Status	REF
Discovery agent	N.A.	Investigative	[6]

KN-62 Interacts with 13 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
LCK tyrosine protein kinase (LCK)	TT860QF	LCK_HUMAN	Inhibitor	[10]
Protein kinase C alpha (PRKCA)	TTFJ8Q1	KPCA_HUMAN	Inhibitor	[10]
Stress-activated protein kinase JNK1 (JNK1)	TT0K6EO	MK08_HUMAN	Inhibitor	[10]
Rho-associated protein kinase 1 (ROCK1)	TTZN7RP	ROCK1_HUMAN	Inhibitor	[10]
Stress-activated protein kinase 2b (p38 beta)	TT73U6C	MK11_HUMAN	Inhibitor	[10]
Extracellular signal-regulated kinase 2 (ERK2)	TT4TQBX	MK01_HUMAN	Inhibitor	[10]
Checkpoint kinase-1 (CHK1)	TTTU902	CHK1_HUMAN	Inhibitor	[10]
P2X purinoceptor 7 (P2RX7)	TT473XN	P2RX7_HUMAN	Inhibitor	[11]
Serine/threonine-protein kinase Sgk1 (SGK1)	TTTV8EJ	SGK1_HUMAN	Inhibitor	[10]
Stress-activated protein kinase 2a (p38 alpha)	TTQBR95	MK14_HUMAN	Inhibitor	[10]
RAC-alpha serine/threonine-protein kinase (AKT1)	TTWTSCV	AKT1_HUMAN	Inhibitor	[10]
MAP kinase p38 (MAPK12)	TTYT93M	MK12_HUMAN	Inhibitor	[10]
Ribosomal protein S6 kinase beta-1 (S6K1)	TTG0U4H	KS6B1_HUMAN	Inhibitor	[10]

KN-62 Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
MAP kinase-activated protein kinase 2 (MAPKAPK2)	OT460SBO	MAPK2_HUMAN	Decreases Activity	[10]
Glycogen synthase kinase-3 beta (GSK3B)	OTL3L14B	GSK3B_HUMAN	Decreases Activity	[10]
MAP kinase-activated protein kinase 5 (MAPKAPK5)	OTAZHPVK	MAPK5_HUMAN	Decreases Activity	[10]
Integrin alpha-M (ITGAM)	OTAG6HWU	ITAM_HUMAN	Increases Expression	[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] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (NDA) 019578
• [3] 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.
• [4] Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob Agents Chemother. 2014 Aug;58(8):4885-93.
• [5] Mefloquine 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: 6001).
• [7] An ultrastructural study of the effects of mefloquine on malaria parasites. Am J Trop Med Hyg. 1987 Jan;36(1):9-14.
• [8] Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther. 2004 Jan;75(1):13-33.
• [9] Effect of rifampin on plasma concentrations of mefloquine in healthy volunteers. J Pharm Pharmacol. 2000 Oct;52(10):1265-9.
• [10] Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000 Oct 1;351(Pt 1):95-105.
• [11] Synthesis and structure-activity relationships of pyrazolodiazepine derivatives as human P2X7 receptor antagonists. Bioorg Med Chem Lett. 2009 Nov 1;19(21):6053-8.
• [12] CaMKII regulates retinoic acid receptor transcriptional activity and the differentiation of myeloid leukemia cells. J Clin Invest. 2007 May;117(5):1412-21. doi: 10.1172/JCI30779. Epub 2007 Apr 12.