Details of the Drug Combination

General Information of Drug Combination (ID: DCZXJZQ)

• Drug Combination Name: BREQUINAR + Dipyridamole
• Indication: COVID-19; Status: Phase 2 [1]
• Component Drugs:
  BREQUINAR (DMKGM42): Small molecular drug
  Dipyridamole (DMXY30O): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of BREQUINAR

Disease Entry	ICD 11	Status	REF
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[2]
Acute myeloid leukaemia	2A60	Phase 1/2	[3]

BREQUINAR Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Dihydroorotate dehydrogenase (DHODH)	TTLVP78	PYRD_HUMAN	Modulator	[6]

Indication(s) of Dipyridamole

Disease Entry	ICD 11	Status	REF
Atrial fibrillation	BC81.3	Approved	[4]
Chronic heart failure	BD1Z	Approved	[4]
Hypertension	BA00-BA04	Approved	[5]
Malignant essential hypertension	BA00	Approved	[4]

Dipyridamole Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Phosphodiesterase 5A (PDE5A)	TTJ0IQB	PDE5A_HUMAN	Modulator	[8]

Dipyridamole Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[9]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[10]

Dipyridamole Interacts with 16 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A)	OTT8Q1AP	PDE5A_HUMAN	Decreases Activity	[11]
Mitogen-activated protein kinase 8 (MAPK8)	OTEREYS5	MK08_HUMAN	Increases Activity	[11]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[12]
ATP-binding cassette sub-family C member 4 (ABCC4)	OTO27PAL	MRP4_HUMAN	Decreases Activity	[13]
Tissue-type plasminogen activator (PLAT)	OTQPDNAB	TPA_HUMAN	Increases Secretion	[14]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Increases Expression	[15]
Alpha-1-acid glycoprotein 1 (ORM1)	OTZKSBRE	A1AG1_HUMAN	Affects Binding	[16]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Affects Activity	[17]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Increases Expression	[18]
CD40 ligand (CD40LG)	OT75Z6A6	CD40L_HUMAN	Decreases Secretion	[19]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[20]
Calcipressin-1 (RCAN1)	OT1MVXC7	RCAN1_HUMAN	Affects Binding	[21]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[20]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[22]
FAS-associated death domain protein (FADD)	OTV7GFHH	FADD_HUMAN	Increases Expression	[23]
Equilibrative nucleoside transporter 1 (SLC29A1)	OTLOOZZS	S29A1_HUMAN	Decreases Activity	[24]

References

• [1] ClinicalTrials.gov (NCT05166876) Brequinar Combined With Dipyridamole in Patients With Mild to Moderate COVID-19
• [2] ClinicalTrials.gov (NCT04575038) CRISIS2: A Phase 2 Study of the Safety and Antiviral Activity of Brequinar in Non-hospitalized Pts With COVID-19 (CRISIS2). U.S. National Institutes of Health.
• [3] ClinicalTrials.gov (NCT03760666) A Study of Brequinar in Subjects With Relapsed/Refractory Acute Myeloid Leukemia. U.S. National Institutes of Health.
• [4] Dipyridamole FDA Label
• [5] 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: 4807).
• [6] DOI: 10.1203/00006450-198807000-00137
• [7] Adenosine up-regulates vascular endothelial growth factor in human macrophages. Biochem Biophys Res Commun. 2010 Feb 12;392(3):351-6. doi: 10.1016/j.bbrc.2010.01.023. Epub 2010 Jan 11.
• [8] Anti-platelet therapy: phosphodiesterase inhibitors.Br J Clin Pharmacol.2011 Oct;72(4):634-46.
• [9] Improving the prediction of the brain disposition for orally administered drugs using BDDCS. Adv Drug Deliv Rev. 2012 Jan;64(1):95-109.
• [10] ABCG2: a perspective. Adv Drug Deliv Rev. 2009 Jan 31;61(1):3-13.
• [11] Cyclic GMP mediates apoptosis induced by sulindac derivatives via activation of c-Jun NH2-terminal kinase 1. Clin Cancer Res. 2000 Oct;6(10):4136-41.
• [12] A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol Sci. 2013 Nov;136(1):216-41.
• [13] Expression of multidrug transporter MRP4/ABCC4 is a marker of poor prognosis in neuroblastoma and confers resistance to irinotecan in vitro. Mol Cancer Ther. 2005 Apr;4(4):547-53. doi: 10.1158/1535-7163.MCT-04-0161.
• [14] Dipyridamole enhances tissue plasminogen activator release by brain capillary endothelial cells. Thromb Res. 2005;115(5):435-8. doi: 10.1016/j.thromres.2004.10.001. Epub 2004 Nov 5.
• [15] Selection of drugs to test the specificity of the Tg.AC assay by screening for induction of the gadd153 promoter in vitro. Toxicol Sci. 2003 Aug;74(2):260-70. doi: 10.1093/toxsci/kfg113. Epub 2003 May 2.
• [16] Binding of disopyramide, methadone, dipyridamole, chlorpromazine, lignocaine and progesterone to the two main genetic variants of human alpha 1-acid glycoprotein: evidence for drug-binding differences between the variants and for the presence of two separate drug-binding sites on alpha 1-acid glycoprotein. Pharmacogenetics. 1996 Oct;6(5):403-15. doi: 10.1097/00008571-199610000-00004.
• [17] Identification of environmental chemicals that activate p53 signaling after in vitro metabolic activation. Arch Toxicol. 2022 Jul;96(7):1975-1987. doi: 10.1007/s00204-022-03291-5. Epub 2022 Apr 18.
• [18] Impact of adenosine receptor signaling and metabolism on pathophysiology in patients with chronic heart failure. Hypertens Res. 2007 Sep;30(9):781-7. doi: 10.1291/hypres.30.781.
• [19] The effect of dipyridamole on vascular cell-derived reactive oxygen species. J Pharmacol Exp Ther. 2005 Nov;315(2):494-500. doi: 10.1124/jpet.105.089987. Epub 2005 Jul 26.
• [20] Palmitate increases the susceptibility of cells to drug-induced toxicity: an in vitro method to identify drugs with potential contraindications in patients with metabolic disease. Toxicol Sci. 2012 Oct;129(2):346-62. doi: 10.1093/toxsci/kfs208. Epub 2012 Jun 14.
• [21] Inhibiting the calcineurin-NFAT (nuclear factor of activated T cells) signaling pathway with a regulator of calcineurin-derived peptide without affecting general calcineurin phosphatase activity. J Biol Chem. 2009 Apr 3;284(14):9394-401. doi: 10.1074/jbc.M805889200. Epub 2009 Feb 3.
• [22] Effects of phosphodiesterase (PDE) inhibitors on human ether-a-go-go related gene (hERG) channel activity. J Appl Toxicol. 2007 Jan-Feb;27(1):78-85. doi: 10.1002/jat.1201.
• [23] Intracellularly transported adenosine induces apoptosis in HuH-7 human hepatoma cells by downregulating c-FLIP expression causing caspase-3/-8 activation. Biochem Pharmacol. 2007 May 15;73(10):1665-75. doi: 10.1016/j.bcp.2007.01.020. Epub 2007 Jan 18.
• [24] New role of the human equilibrative nucleoside transporter 1 (hENT1) in epithelial-to-mesenchymal transition in renal tubular cells. J Cell Physiol. 2012 Apr;227(4):1521-8. doi: 10.1002/jcp.22869.