Details of the Drug Combination

General Information of Drug Combination (ID: DC7K03A)

• Drug Combination Name: Baricitinib + Danazol
• Indication: Immune Thrombocytopenia; Status: Phase 2 [1]
• Component Drugs:
  Baricitinib (DM4ONW5): Small molecular drug
  Danazol (DML8KTN): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Baricitinib

Disease Entry	ICD 11	Status	REF
Rheumatoid arthritis	FA20	Approved	[2]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[3]

Baricitinib Interacts with 5 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
HUMAN cyclin G-associated kinase (GAK)	TT0AGBL	GAK_HUMAN	Inhibitor	[6]
Janus kinase 2 (JAK-2)	TTRMX3V	JAK2_HUMAN	Modulator	[7]
Tyrosine-protein kinase (PTK)	TTJSQEF	NOUNIPROTAC	Inhibitor	[2]
Janus kinase 1 (JAK-1)	TT6DM01	JAK1_HUMAN	Modulator	[7]
HUMAN adaptor-associated kinase 1 (AAK1)	TTN9A16	AAK1_HUMAN	Inhibitor	[6]

Baricitinib Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[8]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[9]

Baricitinib Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[10]

Baricitinib Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cyclin-G-associated kinase (GAK)	OTLM5H4P	GAK_HUMAN	Decreases Activity	[11]
AP2-associated protein kinase 1 (AAK1)	OTK9B9QT	AAK1_HUMAN	Decreases Activity	[11]

Indication(s) of Danazol

Disease Entry	ICD 11	Status	REF
Menorrhagia	GA20.50	Approved	[4]
Breast cancer	2C60-2C65	Phase 2	[4]
Breast fibrocystic disease	N.A.	Investigative	[5]
Endometriosis	GA10	Investigative	[5]

Danazol Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Estrogen receptor (ESR)	TTZAYWL	ESR1_HUMAN	Antagonist	[12]

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	[13]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[14]
Cytochrome P450 2J2 (CYP2J2)	OTJBTEH8	CP2J2_HUMAN	Decreases Activity	[15]
Transmembrane protease serine 2 (TMPRSS2)	OTN44YQ5	TMPS2_HUMAN	Increases Expression	[16]
Complement factor B (CFB)	OTZITNEJ	CFAB_HUMAN	Increases Expression	[17]
Complement C3 (C3)	OTCH5GS0	CO3_HUMAN	Increases Expression	[17]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[18]
Plasma protease C1 inhibitor (SERPING1)	OT6CVN45	IC1_HUMAN	Increases Expression	[17]
Steryl-sulfatase (STS)	OTXTJQPC	STS_HUMAN	Decreases Activity	[19]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Increases Activity	[20]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[21]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Decreases Expression	[16]

References

• [1] ClinicalTrials.gov (NCT05852847) Low-dose Baricitinib Plus Danazol for Steroid-resistant/Relapse Immune Thrombocytopenia
• [2] 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.
• [3] ClinicalTrials.gov (NCT04345289) Efficacy and Safety of Novel Treatment Options for Adults With COVID-19 Pneumonia. U.S. National Institutes of Health.
• [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: 6942).
• [5] Danazol FDA Label
• [6] Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet. 2020 Feb 15;395(10223):e30-e31.
• [7] Selective JAK inhibitors in development for rheumatoid arthritis. Expert Opin Investig Drugs. 2014 Aug;23(8):1067-77.
• [8] Prediction of Transporter-Mediated Drug-Drug Interactions for Baricitinib. Clin Transl Sci. 2017 Nov;10(6):509-519.
• [9] Differential Influence of the Antiretroviral Pharmacokinetic Enhancers Ritonavir and Cobicistat on Intestinal P-Glycoprotein Transport and the Pharmacokinetic/Pharmacodynamic Disposition of Dabigatran. Antimicrob Agents Chemother. 2017 Oct 24;61(11). pii: e01201-17.
• [10] FDA label of Baricitinib. The 2020 official website of the U.S. Food and Drug Administration.
• [11] COVID-19: combining antiviral and anti-inflammatory treatments. Lancet Infect Dis. 2020 Apr;20(4):400-402. doi: 10.1016/S1473-3099(20)30132-8. Epub 2020 Feb 27.
• [12] 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.
• [13] The anabolic androgenic steroid fluoxymesterone inhibits 11beta-hydroxysteroid dehydrogenase 2-dependent glucocorticoid inactivation. Toxicol Sci. 2012 Apr;126(2):353-61.
• [14] A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol Sci. 2013 Nov;136(1):216-41.
• [15] Inhibitory effects of Danshen components on CYP2C8 and CYP2J2. Chem Biol Interact. 2018 Jun 1;289:15-22.
• [16] 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.
• [17] Guillain-Barr syndrome following danazol and corticosteroid therapy for hereditary angioedema. Am J Med. 1985 Jul;79(1):111-4. doi: 10.1016/0002-9343(85)90553-4.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.