Details of the Drug Combination

General Information of Drug Combination (ID: DCX3CHG)

• Drug Combination Name: Teriflunomide + Mycophenolic acid
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Teriflunomide (DMQ2FKJ): Small molecular drug
  Mycophenolic acid (DMRBMAU): N.A.
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 5.16
  Bliss Independence Score: 5.16
  Loewe Additivity Score: 6.09
  LHighest Single Agent (HSA) Score: 6.09

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Teriflunomide

Disease Entry	ICD 11	Status	REF
Hyperlipidaemia	5C80	Approved	[2]
Lupus nephritis	4A40.0Y	Approved	[3]
Multiple sclerosis	8A40	Approved	[4]
Psoriatic arthritis	FA21	Approved	[3]
Rheumatoid arthritis	FA20	Phase 3	[4]
Hepatitis B virus infection	1E51.0	Phase 1	[2]

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	[16]
HMG-CoA reductase (HMGCR)	TTPADOQ	HMDH_HUMAN	Inhibitor	[2]
Dihydroorotate dehydrogenase (DHODH)	TTLVP78	PYRD_HUMAN	Modulator	[17]

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	[18]

Teriflunomide Interacts with 33 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Phenylalanine--tRNA ligase, mitochondrial (FARS2)	OTXAK6F0	SYFM_HUMAN	Decreases Expression	[19]
Ornithine aminotransferase, mitochondrial (OAT)	OTEKO8CT	OAT_HUMAN	Increases Expression	[19]
Heat shock 70 kDa protein 1-like (HSPA1L)	OTC2V1K6	HS71L_HUMAN	Decreases Expression	[19]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[19]
1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1)	OTG2T749	CP24A_HUMAN	Decreases Expression	[19]
BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)	OT4SO7J4	BNIP3_HUMAN	Increases Expression	[19]
Mitochondrial adenyl nucleotide antiporter SLC25A25 (SLC25A25)	OTMNPSNY	SCMC2_HUMAN	Increases Expression	[19]
Mitochondrial fission regulator 2 (MTFR2)	OTLOR68D	MTFR2_HUMAN	Decreases Expression	[19]
Choline dehydrogenase, mitochondrial (CHDH)	OTO2DPGL	CHDH_HUMAN	Decreases Expression	[19]
Dimethyladenosine transferase 1, mitochondrial (TFB1M)	OTFCUSAZ	TFB1M_HUMAN	Decreases Expression	[19]
Probable ATP-dependent RNA helicase DDX28 (DDX28)	OTIIHNYN	DDX28_HUMAN	Decreases Expression	[19]
Glucocorticoid receptor (NR3C1)	OTCI2YDI	GCR_HUMAN	Increases Activity	[20]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[20]
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Increases Expression	[20]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Increases Expression	[20]
Phosphoenolpyruvate carboxykinase, cytosolic (PCK1)	OTNWEJ5Y	PCKGC_HUMAN	Increases Expression	[20]
Glucose-6-phosphatase catalytic subunit 1 (G6PC1)	OTJ6FM9F	G6PC1_HUMAN	Increases Expression	[20]
Fatty acid synthase (FASN)	OTFII9KG	FAS_HUMAN	Decreases Expression	[20]
Nuclear receptor subfamily 1 group I member 3 (NR1I3)	OTS3SGH7	NR1I3_HUMAN	Increases Expression	[20]
Glycophorin-A (GYPA)	OTABU4YV	GLPA_HUMAN	Increases Expression	[21]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[22]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Expression	[23]
Cyclin-A2 (CCNA2)	OTPHHYZJ	CCNA2_HUMAN	Increases Expression	[21]
Ribosomal protein S6 kinase beta-1 (RPS6KB1)	OTAELNGX	KS6B1_HUMAN	Decreases Phosphorylation	[23]
G1/S-specific cyclin-E1 (CCNE1)	OTLD7UID	CCNE1_HUMAN	Decreases Expression	[23]
C-X-C chemokine receptor type 1 (CXCR1)	OT5512B2	CXCR1_HUMAN	Decreases Expression	[22]
G1/S-specific cyclin-D2 (CCND2)	OTDULQF9	CCND2_HUMAN	Decreases Expression	[23]
M-phase inducer phosphatase 1 (CDC25A)	OTSLKKCO	MPIP1_HUMAN	Decreases Expression	[23]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Phosphorylation	[23]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[21]
Heat shock factor protein 1 (HSF1)	OTYNJ4KP	HSF1_HUMAN	Increases Activity	[24]
Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1)	OTHBQVD5	4EBP1_HUMAN	Decreases Phosphorylation	[23]
Interleukin-10 receptor subunit alpha (IL10RA)	OTOX3D1D	I10R1_HUMAN	Increases Expression	[22]

Indication(s) of Mycophenolic acid

Disease Entry	ICD 11	Status	REF
Crohn disease	DD70	Approved	[5]
Hepatosplenic T-cell lymphoma	N.A.	Approved	[6]
Interstitial cystitis	GC00.3	Approved	[7]
Large granular lymphocytic leukemia	2A90.1	Approved	[6]
Leukemia	N.A.	Approved	[8]
Lupus nephritis	4A40.0Y	Approved	[9]
MALT lymphoma	N.A.	Approved	[6]
Myeloid leukaemia	2B33.1	Approved	[10]
Myeloproliferative neoplasm	2A20	Approved	[11]
Nodal marginal zone lymphoma	2A85.0	Approved	[6]
Primary cutaneous peripheral T-cell lymphoma not otherwise specified	N.A.	Approved	[6]
Recurrent adult burkitt lymphoma	2A85.6	Approved	[6]
Small intestine lymphoma	N.A.	Approved	[6]
Splenic marginal zone lymphoma	N.A.	Approved	[6]
Systemic lupus erythematosus	4A40.0	Approved	[12]
Testicular lymphoma	N.A.	Approved	[6]
Classic Hodgkin lymphoma	N.A.	Investigative	[13]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Investigative	[14]
Middle East Respiratory Syndrome (MERS)	1D64	Investigative	[15]

Mycophenolic acid Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
MERS-CoV papain-like proteinase (PL-PRO)	TTYJOLE	R1AB_CVEMC (854-2740)	Inhibitor	[15]

Mycophenolic acid Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[25]
Organic anion transporter 1 (SLC22A6)	DTQ23VB	S22A6_HUMAN	Substrate	[26]

Mycophenolic acid Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[27]
UDP-glucuronosyltransferase 1A9 (UGT1A9)	DE85D2P	UD19_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] Emerging drugs in peripheral arterial disease. Expert Opin Emerg Drugs. 2006 Mar;11(1):75-90.
• [3] Teriflunomide FDA Label
• [4] 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).
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [6] A standard database for drug repositioning. Sci Data. 2017 Mar 14;4:170029.
• [7] Early termination of a trial of mycophenolate mofetil for treatment of interstitial cystitis/painful bladder syndrome: lessons learned. J Urol. 2011 Mar;185(3):901-6.
• [8] New conjugates of mycophenolic acid and their antiproliferative activity. J Asian Nat Prod Res. 2016 Nov;18(11):1057-62.
• [9] 2019 Update of the Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of lupus nephritis. Ann Rheum Dis. 2020 Jun;79(6):713-723.
• [10] Mycophenolic Acid overcomes imatinib and nilotinib resistance of chronic myeloid leukemia cells by apoptosis or a senescent-like cell cycle arrest. Leuk Res Treatment. 2012;2012:861301.
• [11] Thiotepa, Busulfan, and Fludarabine Conditioning Regimen in T Cell-Replete HLA-Haploidentical Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2019 Jul;25(7):1407-1415.
• [12] Systemic Lupus Erythematosus Management in Pregnancy. Int J Womens Health. 2022 Feb 15;14:199-211.
• [13] Identification of potential drugs for diffuse large b-cell lymphoma based on bioinformatics and Connectivity Map database. Pathol Res Pract. 2018 Nov;214(11):1854-1867.
• [14] Associations between immune-suppressive and stimulating drugs and novel COVID-19-a systematic review of current evidence. Ecancermedicalscience. 2020 Mar 27;14:1022.
• [15] SARS and MERS: recent insights into emerging coronaviruses. Nat Rev Microbiol. 2016 Aug;14(8):523-34.
• [16] 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.
• [17] Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
• [18] MDR-ABC transporters: biomarkers in rheumatoid arthritis. Clin Exp Rheumatol. 2013 Sep-Oct;31(5):779-87.
• [19] Mitochondrial dysfunction induced by leflunomide and its active metabolite. Toxicology. 2018 Mar 1;396-397:33-45.
• [20] Teriflunomide is an indirect human constitutive androstane receptor (CAR) activator interacting with epidermal growth factor (EGF) signaling. Front Pharmacol. 2018 Oct 11;9:993.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] C-440T/T-331C polymorphisms in the UGT1A9 gene affect the pharmacokinetics of mycophenolic acid in kidney transplantation. Pharmacogenomics. 2007 Sep;8(9):1127-41.
• [26] Interaction and transport characteristics of mycophenolic acid and its glucuronide via human organic anion transporters hOAT1 and hOAT3. Biochem Pharmacol. 2007 Jun 30;74(1):161-8.
• [27] Diabetes mellitus reduces activity of human UDP-glucuronosyltransferase 2B7 in liver and kidney leading to decreased formation of mycophenolic acid acyl-glucuronide metabolite. Drug Metab Dispos. 2011 Mar;39(3):448-55.