Details of the Drug Combination

General Information of Drug Combination (ID: DCQ1YXO)

• Drug Combination Name: Danazol + Teriflunomide
• Indication: Immune Thrombocytopenia; Status: Phase 2 [1]
• Component Drugs:
  Danazol (DML8KTN): Small molecular drug
  Teriflunomide (DMQ2FKJ): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Danazol

Disease Entry	ICD 11	Status	REF
Menorrhagia	GA20.50	Approved	[2]
Breast cancer	2C60-2C65	Phase 2	[2]
Breast fibrocystic disease	N.A.	Investigative	[3]
Endometriosis	GA10	Investigative	[3]

Danazol Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Estrogen receptor (ESR)	TTZAYWL	ESR1_HUMAN	Antagonist	[7]

Danazol Interacts with 12 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
11-beta-hydroxysteroid dehydrogenase type 2 (HSD11B2)	OTHF4H9U	DHI2_HUMAN	Decreases Activity	[8]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[9]
Cytochrome P450 2J2 (CYP2J2)	OTJBTEH8	CP2J2_HUMAN	Decreases Activity	[10]
Transmembrane protease serine 2 (TMPRSS2)	OTN44YQ5	TMPS2_HUMAN	Increases Expression	[11]
Complement factor B (CFB)	OTZITNEJ	CFAB_HUMAN	Increases Expression	[12]
Complement C3 (C3)	OTCH5GS0	CO3_HUMAN	Increases Expression	[12]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[13]
Plasma protease C1 inhibitor (SERPING1)	OT6CVN45	IC1_HUMAN	Increases Expression	[12]
Steryl-sulfatase (STS)	OTXTJQPC	STS_HUMAN	Decreases Activity	[14]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Increases Activity	[15]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[16]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Decreases Expression	[11]

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	[17]
HMG-CoA reductase (HMGCR)	TTPADOQ	HMDH_HUMAN	Inhibitor	[4]
Dihydroorotate dehydrogenase (DHODH)	TTLVP78	PYRD_HUMAN	Modulator	[18]

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	[19]

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

References

• [1] ClinicalTrials.gov (NCT06176911) The Combination of Teriflunomide and Danazol for Steroid-resistant/Relapse Immune Thrombocytopenia
• [2] 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: 6942).
• [3] Danazol FDA Label
• [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] Danazol suppression of luteinizing hormone in the rat: evidence for mediation by both androgen and estrogen receptors. Proc Soc Exp Biol Med. 1990 May;194(1):54-7.
• [8] The anabolic androgenic steroid fluoxymesterone inhibits 11beta-hydroxysteroid dehydrogenase 2-dependent glucocorticoid inactivation. Toxicol Sci. 2012 Apr;126(2):353-61.
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• [11] Effect of common medications on the expression of SARS-CoV-2 entry receptors in liver tissue. Arch Toxicol. 2020 Dec;94(12):4037-4041. doi: 10.1007/s00204-020-02869-1. Epub 2020 Aug 17.
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• [13] Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury. J Toxicol Sci. 2021;46(4):167-176. doi: 10.2131/jts.46.167.
• [14] Synthesis and steroid sulphatase inhibitory activity of C19- and C21-steroidal derivatives bearing a benzyl-inhibiting group. Eur J Med Chem. 2001 Jul-Aug;36(7-8):659-71. doi: 10.1016/s0223-5234(01)01262-4.
• [15] Chemical genomics profiling of environmental chemical modulation of human nuclear receptors. Environ Health Perspect. 2011 Aug;119(8):1142-8. doi: 10.1289/ehp.1002952. Epub 2011 May 4.
• [16] High-content imaging-based BAC-GFP toxicity pathway reporters to assess chemical adversity liabilities. Arch Toxicol. 2017 Mar;91(3):1367-1383. doi: 10.1007/s00204-016-1781-0. Epub 2016 Jun 29.
• [17] 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.
• [18] Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
• [19] MDR-ABC transporters: biomarkers in rheumatoid arthritis. Clin Exp Rheumatol. 2013 Sep-Oct;31(5):779-87.
• [20] Mitochondrial dysfunction induced by leflunomide and its active metabolite. Toxicology. 2018 Mar 1;396-397:33-45.
• [21] Teriflunomide is an indirect human constitutive androstane receptor (CAR) activator interacting with epidermal growth factor (EGF) signaling. Front Pharmacol. 2018 Oct 11;9:993.
• [22] 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.
• [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.
• [24] 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.
• [25] 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.