Details of the Drug Combination

General Information of Drug Combination (ID: DCWYLTX)

• Drug Combination Name: Amodiaquine + Teriflunomide
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Amodiaquine (DME4RA8): Small molecular drug
  Teriflunomide (DMQ2FKJ): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 3.01
  Bliss Independence Score: 3.01
  Loewe Additivity Score: 18.42
  LHighest Single Agent (HSA) Score: 18.42

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Amodiaquine

Disease Entry	ICD 11	Status	REF
Malaria	1F40-1F45	Approved	[2]
Middle East Respiratory Syndrome (MERS)	1D64	Preclinical	[3]
Severe acute respiratory syndrome (SARS)	1D65	Preclinical	[3]

Amodiaquine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Histamine N-methyltransferase (HNMT)	TT2B6EV	HNMT_HUMAN	Inhibitor	[7]

Amodiaquine Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Metabolism	[8]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[9]
Cytochrome P450 1B1 (CYP1B1)	DE9QHP6	CP1B1_HUMAN	Metabolism	[8]
Glutathione S-transferase mu-4 (GSTM4)	DERQ52Z	GSTM4_HUMAN	Metabolism	[10]
Cytochrome P450 102A1 (cyp102)	DE4OGUF	CPXB_BACMB	Metabolism	[11]

Amodiaquine Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Activity	[12]
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Increases Expression	[13]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Affects Phosphorylation	[14]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Expression	[13]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Affects Expression	[14]
Tumor necrosis factor-inducible gene 6 protein (TNFAIP6)	OT1SLUZH	TSG6_HUMAN	Decreases Expression	[13]
Transcription factor E2F1 (E2F1)	OTLKYBBC	E2F1_HUMAN	Affects Expression	[14]
PTB-containing, cubilin and LRP1-interacting protein (PID1)	OT5YJ7FI	PCLI1_HUMAN	Increases Expression	[13]

Indication(s) of Teriflunomide

Disease Entry	ICD 11	Status	REF
Hyperlipidaemia	5C80	Approved	[4]
Lupus nephritis	4A40.0Y	Approved	[5]
Multiple sclerosis	8A40	Approved	[6]
Psoriatic arthritis	FA21	Approved	[5]
Rheumatoid arthritis	FA20	Phase 3	[6]
Hepatitis B virus infection	1E51.0	Phase 1	[4]

Teriflunomide Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Plasmodium Dihydroorotate dehydrogenase (Malaria DHOdehase)	TT3PQ2Y	PYRD_PLAF7	Inhibitor	[15]
HMG-CoA reductase (HMGCR)	TTPADOQ	HMDH_HUMAN	Inhibitor	[4]
Dihydroorotate dehydrogenase (DHODH)	TTLVP78	PYRD_HUMAN	Modulator	[16]

Teriflunomide Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[17]

Teriflunomide Interacts with 20 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Ornithine aminotransferase, mitochondrial (OAT)	OTEKO8CT	OAT_HUMAN	Increases Expression	[18]
Heat shock 70 kDa protein 1-like (HSPA1L)	OTC2V1K6	HS71L_HUMAN	Decreases Expression	[18]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[18]
1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1)	OTG2T749	CP24A_HUMAN	Decreases Expression	[18]
BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)	OT4SO7J4	BNIP3_HUMAN	Increases Expression	[18]
Mitochondrial adenyl nucleotide antiporter SLC25A25 (SLC25A25)	OTMNPSNY	SCMC2_HUMAN	Increases Expression	[18]
Mitochondrial fission regulator 2 (MTFR2)	OTLOR68D	MTFR2_HUMAN	Decreases Expression	[18]
Choline dehydrogenase, mitochondrial (CHDH)	OTO2DPGL	CHDH_HUMAN	Decreases Expression	[18]
Dimethyladenosine transferase 1, mitochondrial (TFB1M)	OTFCUSAZ	TFB1M_HUMAN	Decreases Expression	[18]
Probable ATP-dependent RNA helicase DDX28 (DDX28)	OTIIHNYN	DDX28_HUMAN	Decreases Expression	[18]
Phosphoenolpyruvate carboxykinase, cytosolic (PCK1)	OTNWEJ5Y	PCKGC_HUMAN	Increases Expression	[19]
Glucose-6-phosphatase catalytic subunit 1 (G6PC1)	OTJ6FM9F	G6PC1_HUMAN	Increases Expression	[19]
Nuclear receptor subfamily 1 group I member 3 (NR1I3)	OTS3SGH7	NR1I3_HUMAN	Increases Expression	[19]
Glycophorin-A (GYPA)	OTABU4YV	GLPA_HUMAN	Increases Expression	[20]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Expression	[21]
G1/S-specific cyclin-D2 (CCND2)	OTDULQF9	CCND2_HUMAN	Decreases Expression	[21]
M-phase inducer phosphatase 1 (CDC25A)	OTSLKKCO	MPIP1_HUMAN	Decreases Expression	[21]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[20]
Heat shock factor protein 1 (HSF1)	OTYNJ4KP	HSF1_HUMAN	Increases Activity	[22]
Interleukin-10 receptor subunit alpha (IL10RA)	OTOX3D1D	I10R1_HUMAN	Increases Expression	[23]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [2] Drug information of Amodiaquine, 2008. eduDrugs.
• [3] Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob Agents Chemother. 2014 Aug;58(8):4885-93.
• [4] Emerging drugs in peripheral arterial disease. Expert Opin Emerg Drugs. 2006 Mar;11(1):75-90.
• [5] Teriflunomide 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: 6844).
• [7] Effect of amodiaquine, a histamine N-methyltransferase inhibitor, on, Propionibacterium acnes and lipopolysaccharide-induced hepatitis in mice. Eur J Pharmacol. 2007 Mar 8;558(1-3):179-84.
• [8] Amodiaquine clearance and its metabolism to N-desethylamodiaquine is mediated by CYP2C8: a new high affinity and turnover enzyme-specific probe substrate. J Pharmacol Exp Ther. 2002 Feb;300(2):399-407.
• [9] Amodiaquine metabolism is impaired by common polymorphisms in CYP2C8: implications for malaria treatment in Africa. Clin Pharmacol Ther. 2007 Aug;82(2):197-203.
• [10] Human glutathione S-transferases- and NAD(P)H:quinone oxidoreductase 1-catalyzed inactivation of reactive quinoneimines of amodiaquine and N-desethylamodiaquine: possible implications for susceptibility to amodiaquine-induced liver toxicity. Toxicol Lett. 2017 Jun 5;275:83-91.
• [11] The bacterial P450 BM3: a prototype for a biocatalyst with human P450 activities. Trends Biotechnol. 2007 Jul;25(7):289-98.
• [12] Application of higher throughput screening (HTS) inhibition assays to evaluate the interaction of antiparasitic drugs with cytochrome P450s. Drug Metab Dispos. 2001 Jan;29(1):30-5.
• [13] 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.
• [14] The antimalarial amodiaquine causes autophagic-lysosomal and proliferative blockade sensitizing human melanoma cells to starvation- and chemotherapy-induced cell death. Autophagy. 2013 Dec;9(12):2087-102. doi: 10.4161/auto.26506. Epub 2013 Oct 8.
• [15] Expression and characterization of E. coli-produced soluble, functional human dihydroorotate dehydrogenase: a potential target for immunosuppression. J Mol Microbiol Biotechnol. 1999 Aug;1(1):183-8.
• [16] Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
• [17] MDR-ABC transporters: biomarkers in rheumatoid arthritis. Clin Exp Rheumatol. 2013 Sep-Oct;31(5):779-87.
• [18] Mitochondrial dysfunction induced by leflunomide and its active metabolite. Toxicology. 2018 Mar 1;396-397:33-45.
• [19] Teriflunomide is an indirect human constitutive androstane receptor (CAR) activator interacting with epidermal growth factor (EGF) signaling. Front Pharmacol. 2018 Oct 11;9:993.
• [20] A77 1726 induces differentiation of human myeloid leukemia K562 cells by depletion of intracellular CTP pools. Mol Pharmacol. 2002 Sep;62(3):463-72. doi: 10.1124/mol.62.3.463.
• [21] Dihydroorotate dehydrogenase inhibitor A771726 (leflunomide) induces apoptosis and diminishes proliferation of multiple myeloma cells. Mol Cancer Ther. 2009 Feb;8(2):366-75. doi: 10.1158/1535-7163.MCT-08-0664. Epub 2009 Jan 27.
• [22] A Gene Expression Biomarker Predicts Heat Shock Factor 1 Activation in a Gene Expression Compendium. Chem Res Toxicol. 2021 Jul 19;34(7):1721-1737. doi: 10.1021/acs.chemrestox.0c00510. Epub 2021 Jun 25.
• [23] Differential modulation of pro- and anti-inflammatory cytokine receptors by N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxy-crotonic acid amide (A77 1726), the physiologically active metabolite of the novel immunomodulator leflunomide. Biochem Pharmacol. 1998 May 1;55(9):1523-9. doi: 10.1016/s0006-2952(97)00677-1.