Details of the Drug Combination

General Information of Drug Combination (ID: DCV0N0Q)

• Drug Combination Name: Teriflunomide + Selumetinib
• Indication: Diffuse intrinsic pontine glioma; Status: Investigative [1]
• Component Drugs:
  Teriflunomide (DMQ2FKJ): Small molecular drug
  Selumetinib (DMC7W6R): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: DIPG25
  Zero Interaction Potency (ZIP) Score: 2.256
  Bliss Independence Score: 10.892
  Loewe Additivity Score: 2.631
  LHighest Single Agent (HSA) Score: 3.881

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	[11]
HMG-CoA reductase (HMGCR)	TTPADOQ	HMDH_HUMAN	Inhibitor	[2]
Dihydroorotate dehydrogenase (DHODH)	TTLVP78	PYRD_HUMAN	Modulator	[12]

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	[13]

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	[14]
Ornithine aminotransferase, mitochondrial (OAT)	OTEKO8CT	OAT_HUMAN	Increases Expression	[14]
Heat shock 70 kDa protein 1-like (HSPA1L)	OTC2V1K6	HS71L_HUMAN	Decreases Expression	[14]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[14]
1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1)	OTG2T749	CP24A_HUMAN	Decreases Expression	[14]
BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)	OT4SO7J4	BNIP3_HUMAN	Increases Expression	[14]
Mitochondrial adenyl nucleotide antiporter SLC25A25 (SLC25A25)	OTMNPSNY	SCMC2_HUMAN	Increases Expression	[14]
Mitochondrial fission regulator 2 (MTFR2)	OTLOR68D	MTFR2_HUMAN	Decreases Expression	[14]
Choline dehydrogenase, mitochondrial (CHDH)	OTO2DPGL	CHDH_HUMAN	Decreases Expression	[14]
Dimethyladenosine transferase 1, mitochondrial (TFB1M)	OTFCUSAZ	TFB1M_HUMAN	Decreases Expression	[14]
Probable ATP-dependent RNA helicase DDX28 (DDX28)	OTIIHNYN	DDX28_HUMAN	Decreases Expression	[14]
Glucocorticoid receptor (NR3C1)	OTCI2YDI	GCR_HUMAN	Increases Activity	[15]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[15]
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Increases Expression	[15]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Increases Expression	[15]
Phosphoenolpyruvate carboxykinase, cytosolic (PCK1)	OTNWEJ5Y	PCKGC_HUMAN	Increases Expression	[15]
Glucose-6-phosphatase catalytic subunit 1 (G6PC1)	OTJ6FM9F	G6PC1_HUMAN	Increases Expression	[15]
Fatty acid synthase (FASN)	OTFII9KG	FAS_HUMAN	Decreases Expression	[15]
Nuclear receptor subfamily 1 group I member 3 (NR1I3)	OTS3SGH7	NR1I3_HUMAN	Increases Expression	[15]
Glycophorin-A (GYPA)	OTABU4YV	GLPA_HUMAN	Increases Expression	[16]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[17]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Expression	[18]
Cyclin-A2 (CCNA2)	OTPHHYZJ	CCNA2_HUMAN	Increases Expression	[16]
Ribosomal protein S6 kinase beta-1 (RPS6KB1)	OTAELNGX	KS6B1_HUMAN	Decreases Phosphorylation	[18]
G1/S-specific cyclin-E1 (CCNE1)	OTLD7UID	CCNE1_HUMAN	Decreases Expression	[18]
C-X-C chemokine receptor type 1 (CXCR1)	OT5512B2	CXCR1_HUMAN	Decreases Expression	[17]
G1/S-specific cyclin-D2 (CCND2)	OTDULQF9	CCND2_HUMAN	Decreases Expression	[18]
M-phase inducer phosphatase 1 (CDC25A)	OTSLKKCO	MPIP1_HUMAN	Decreases Expression	[18]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Phosphorylation	[18]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[16]
Heat shock factor protein 1 (HSF1)	OTYNJ4KP	HSF1_HUMAN	Increases Activity	[19]
Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1)	OTHBQVD5	4EBP1_HUMAN	Decreases Phosphorylation	[18]
Interleukin-10 receptor subunit alpha (IL10RA)	OTOX3D1D	I10R1_HUMAN	Increases Expression	[17]

Indication(s) of Selumetinib

Disease Entry	ICD 11	Status	REF
Neurofibromatosis type 1	LD2D.10	Approved	[5]
Melanoma	2C30	Phase 3	[6]
Thyroid cancer	2D10	Phase 3	[7]
Non-small-cell lung cancer	2C25.Y	Phase 2	[8]
Middle East Respiratory Syndrome (MERS)	1D64	Investigative	[9]
Severe acute respiratory syndrome (SARS)	1D65	Investigative	[9]
Solid tumour/cancer	2A00-2F9Z	Investigative	[10]

Selumetinib Interacts with 5 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
MAPK/ERK kinase kinase (MAP3K)	TTROQ37	NOUNIPROTAC	Modulator	[20]
ERK activator kinase 1 (MEK1)	TTIDAPM	MP2K1_HUMAN	Inhibitor	[7]
ERK activator kinase 2 (MEK2)	TTTW2NY	MP2K2_HUMAN	Inhibitor	[7]
HUMAN ERK activator kinase 1 (MEK1)	TTAW3TO	MP2K1_HUMAN	Inhibitor	[9]
HUMAN ERK activator kinase 2 (MEK2)	TTWX403	MP2K2_HUMAN	Inhibitor	[9]

Selumetinib Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[21]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Decreases Phosphorylation	[22]
Interstitial collagenase (MMP1)	OTI4I2V1	MMP1_HUMAN	Decreases Activity	[22]
72 kDa type IV collagenase (MMP2)	OT5NIWA2	MMP2_HUMAN	Decreases Activity	[22]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Decreases Activity	[22]
Cyclic AMP-responsive element-binding protein 1 (CREB1)	OT1MDLA1	CREB1_HUMAN	Decreases Phosphorylation	[22]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[23]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[23]

References

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• [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] ClinicalTrials.gov (NCT01933932) Assess Efficacy & Safety of Selumetinib in Combination With Docetaxel in Patients Receiving 2nd Line Treatment for v-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Positive NSCLC (SELECT-1)
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] 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: 5665).
• [9] Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov. 2016 May;15(5):327-47.
• [10] 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. (Target id: 1479).
• [11] 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.
• [12] Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
• [13] MDR-ABC transporters: biomarkers in rheumatoid arthritis. Clin Exp Rheumatol. 2013 Sep-Oct;31(5):779-87.
• [14] Mitochondrial dysfunction induced by leflunomide and its active metabolite. Toxicology. 2018 Mar 1;396-397:33-45.
• [15] Teriflunomide is an indirect human constitutive androstane receptor (CAR) activator interacting with epidermal growth factor (EGF) signaling. Front Pharmacol. 2018 Oct 11;9:993.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Intrinsic resistance to selumetinib, a selective inhibitor of MEK1/2, by cAMP-dependent protein kinase A activation in human lung and colorectal cancer cells.Br J Cancer.2012 May 8;106(10):1648-59.
• [21] Antitumor action of the MET tyrosine kinase inhibitor crizotinib (PF-02341066) in gastric cancer positive for MET amplification. Mol Cancer Ther. 2012 Jul;11(7):1557-64. doi: 10.1158/1535-7163.MCT-11-0934. Epub 2012 Jun 22.
• [22] Ursonic acid exerts inhibitory effects on matrix metalloproteinases via ERK signaling pathway. Chem Biol Interact. 2020 Jan 5;315:108910. doi: 10.1016/j.cbi.2019.108910. Epub 2019 Nov 29.
• [23] The synergistic interaction of MEK and PI3K inhibitors is modulated by mTOR inhibition. Br J Cancer. 2012 Apr 10;106(8):1386-94. doi: 10.1038/bjc.2012.70. Epub 2012 Mar 13.