Details of the Drug Combination

General Information of Drug Combination (ID: DCT1CR2)

• Drug Combination Name: Bafilomycin A1 + Mefloquine
• Indication: DD2; Status: Investigative [1]
• Component Drugs:
  Bafilomycin A1 (DMUNK59): Small molecular drug
  Mefloquine (DMWT905): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: DD2
  Zero Interaction Potency (ZIP) Score: 1.808
  Bliss Independence Score: 2.604
  Loewe Additivity Score: 0.423
  LHighest Single Agent (HSA) Score: 3.74

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Bafilomycin A1

Disease Entry	ICD 11	Status	REF
B-cell acute lymphoblastic leukaemia	2B33.3	Investigative	[2]

Bafilomycin A1 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Vacuolar-type proton ATPase (v-ATPase)	TTTK3BH	NOUNIPROTAC	Inhibitor	[8]

Bafilomycin A1 Interacts with 24 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Apoptotic protease-activating factor 1 (APAF1)	OTJWIVY0	APAF_HUMAN	Increases Expression	[9]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Expression	[9]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Expression	[9]
Steroidogenic factor 1 (NR5A1)	OTOULYR4	STF1_HUMAN	Decreases Expression	[10]
Nuclear factor erythroid 2-related factor 2 (NFE2L2)	OT0HENJ5	NF2L2_HUMAN	Increases Expression	[11]
Zinc finger protein SNAI1 (SNAI1)	OTDPYAMC	SNAI1_HUMAN	Increases Expression	[7]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Decreases Uptake	[12]
Cathepsin D (CTSD)	OTQZ36F3	CATD_HUMAN	Decreases Cleavage	[13]
Procathepsin L (CTSL)	OTYTUW29	CATL1_HUMAN	Decreases Cleavage	[13]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Decreases Expression	[14]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[15]
Gap junction alpha-1 protein (GJA1)	OTT94MKL	CXA1_HUMAN	Increases Expression	[16]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Decreases Activity	[17]
Caspase-4 (CASP4)	OTVQTV1L	CASP4_HUMAN	Increases Activity	[18]
Microsomal triglyceride transfer protein large subunit (MTTP)	OTNUVSDT	MTP_HUMAN	Increases Expression	[19]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Decreases Activity	[17]
BH3-interacting domain death agonist (BID)	OTOSHSHU	BID_HUMAN	Increases Cleavage	[20]
BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)	OT4SO7J4	BNIP3_HUMAN	Increases Expression	[17]
Sequestosome-1 (SQSTM1)	OTGY5D5J	SQSTM_HUMAN	Increases Expression	[21]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Increases Expression	[17]
NACHT, LRR and PYD domains-containing protein 3 (NLRP3)	OTZM6MHU	NLRP3_HUMAN	Increases Expression	[7]
Microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B)	OTUYHB84	MLP3B_HUMAN	Increases Cleavage	[22]
Microtubule-associated proteins 1A/1B light chain 3A (MAP1LC3A)	OTPMGIU4	MLP3A_HUMAN	Increases Expression	[23]
Leucine-rich repeat serine/threonine-protein kinase 2 (LRRK2)	OTLS7C99	LRRK2_HUMAN	Increases Response To Substance	[24]

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	[25]

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	[26]

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	[27]

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] Bafilomycin A1 targets both autophagy and apoptosis pathways in pediatric B-cell acute lymphoblastic leukemia. Haematologica. 2015 Mar;100(3):345-56.
• [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] Autophagy mediates bronchial cell malignant transformation induced by chronic arsenic exposure via MEK/ERK1/2 pathway. Toxicol Lett. 2020 Oct 10;332:155-163. doi: 10.1016/j.toxlet.2020.06.006. Epub 2020 Jul 6.
• [8] Molecular basis of V-ATPase inhibition by bafilomycin A1. Nat Commun. 2021 Mar 19;12(1):1782.
• [9] Nano-sized iron particles may induce multiple pathways of cell death following generation of mistranscripted RNA in human corneal epithelial cells. Toxicol In Vitro. 2017 Aug;42:348-357.
• [10] Autophagy as a compensation mechanism participates in ethanol-induced fetal adrenal dysfunction in female rats. Toxicol Appl Pharmacol. 2018 Apr 15;345:36-47.
• [11] Vitamin D protects against particles-caused lung injury through induction of autophagy in an Nrf2-dependent manner. Environ Toxicol. 2019 May;34(5):594-609.
• [12] Chronic high glucose inhibits albumin reabsorption by lysosomal alkalinization in cultured porcine proximal tubular epithelial cells (LLC-PK1). Diabetes Res Clin Pract. 2006 Jun;72(3):223-30. doi: 10.1016/j.diabres.2005.10.019. Epub 2005 Nov 28.
• [13] Berbamine Hydrochloride inhibits lysosomal acidification by activating Nox2 to potentiate chemotherapy-induced apoptosis via the ROS-MAPK pathway in human lung carcinoma cells. Cell Biol Toxicol. 2023 Aug;39(4):1297-1317. doi: 10.1007/s10565-022-09756-8. Epub 2022 Sep 7.
• [14] SB202190 inhibits endothelial cell apoptosis via induction of autophagy and heme oxygenase-1. Oncotarget. 2018 May 1;9(33):23149-23163. doi: 10.18632/oncotarget.25234. eCollection 2018 May 1.
• [15] 5-Methoxyflavanone induces cell cycle arrest at the G2/M phase, apoptosis and autophagy in HCT116 human colon cancer cells. Toxicol Appl Pharmacol. 2011 Aug 1;254(3):288-98. doi: 10.1016/j.taap.2011.05.003. Epub 2011 May 15.
• [16] GJA1 reverses arsenic-induced EMT via modulating MAPK/ERK signaling pathway. Toxicol Appl Pharmacol. 2022 Sep 1;450:116138. doi: 10.1016/j.taap.2022.116138. Epub 2022 Jun 21.
• [17] Combined effects of EGFR tyrosine kinase inhibitors and vATPase inhibitors in NSCLC cells. Toxicol Appl Pharmacol. 2015 Aug 15;287(1):17-25. doi: 10.1016/j.taap.2015.05.001. Epub 2015 May 14.
• [18] Autophagy induction by capsaicin in malignant human breast cells is modulated by p38 and extracellular signal-regulated mitogen-activated protein kinases and retards cell death by suppressing endoplasmic reticulum stress-mediated apoptosis. Mol Pharmacol. 2010 Jul;78(1):114-25. doi: 10.1124/mol.110.063495. Epub 2010 Apr 6.
• [19] Cadmium induces triglyceride levels via microsomal triglyceride transfer protein (MTTP) accumulation caused by lysosomal deacidification regulated by endoplasmic reticulum (ER) Ca(2+) homeostasis. Chem Biol Interact. 2021 Oct 1;348:109649. doi: 10.1016/j.cbi.2021.109649. Epub 2021 Sep 10.
• [20] Inhibition of cholesterol metabolism underlies synergy between mTOR pathway inhibition and chloroquine in bladder cancer cells. Oncogene. 2016 Aug 25;35(34):4518-28. doi: 10.1038/onc.2015.511. Epub 2016 Feb 8.
• [21] Resveratrol-activated AMPK/SIRT1/autophagy in cellular models of Parkinson's disease. Neurosignals. 2011;19(3):163-74. doi: 10.1159/000328516. Epub 2011 Jul 22.
• [22] LncRNA UCA1 attenuates autophagy-dependent cell death through blocking autophagic flux under arsenic stress. Toxicol Lett. 2018 Mar 1;284:195-204. doi: 10.1016/j.toxlet.2017.12.009. Epub 2017 Dec 15.
• [23] Transcriptomic Landscape of Cisplatin-Resistant Neuroblastoma Cells. Cells. 2019 Mar 12;8(3):235. doi: 10.3390/cells8030235.
• [24] G2019S LRRK2 mutant fibroblasts from Parkinson's disease patients show increased sensitivity to neurotoxin 1-methyl-4-phenylpyridinium dependent of autophagy. Toxicology. 2014 Oct 3;324:1-9. doi: 10.1016/j.tox.2014.07.001. Epub 2014 Jul 10.
• [25] An ultrastructural study of the effects of mefloquine on malaria parasites. Am J Trop Med Hyg. 1987 Jan;36(1):9-14.
• [26] Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther. 2004 Jan;75(1):13-33.
• [27] Effect of rifampin on plasma concentrations of mefloquine in healthy volunteers. J Pharm Pharmacol. 2000 Oct;52(10):1265-9.