Details of the Drug Combination

General Information of Drug Combination (ID: DCXADT2)

• Drug Combination Name: Regadenoson + Adenosine
• Indication: Hypertrophic Cardiomyopathy; Status: Phase 4 [1]
• Component Drugs:
  Regadenoson (DM76VHG): Small molecular drug
  Adenosine (DMM2NSK): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Regadenoson

Disease Entry	ICD 11	Status	REF
Radionuclide imaging	N.A.	Approved	[2]

Regadenoson Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adenosine A2a receptor (ADORA2A)	TTM2AOE	AA2AR_HUMAN	Modulator	[4]

Indication(s) of Adenosine

Disease Entry	ICD 11	Status	REF
Paroxysmal supraventricular tachycardia	BC81.Z	Approved	[3]

Adenosine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adenosine A2b receptor (ADORA2B)	TTNE7KG	AA2BR_HUMAN	Modulator	[6]

Adenosine Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 5 (ABCC5)	DTYVM24	MRP5_HUMAN	Substrate	[7]
Equilibrative nucleoside transporter 1 (SLC29A1)	DTXD1TQ	S29A1_HUMAN	Substrate	[8]

Adenosine Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Sulfotransferase 1A1 (SULT1A1)	DEYWLRK	ST1A1_HUMAN	Metabolism	[9]
Adenosine aminohydrolase (ADA)	DEDQHBV	ADA_HUMAN	Metabolism	[10]

Adenosine Interacts with 28 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Equilibrative nucleoside transporter 1 (SLC29A1)	OTLOOZZS	S29A1_HUMAN	Increases Uptake	[11]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[12]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[12]
CASP8 and FADD-like apoptosis regulator (CFLAR)	OTX14BAS	CFLAR_HUMAN	Decreases Expression	[13]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Increases Expression	[14]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Increases Expression	[14]
Adenosine receptor A3 (ADORA3)	OTHO1BLK	AA3R_HUMAN	Increases Expression	[5]
Adenosine receptor A2a (ADORA2A)	OTVRBZ0I	AA2AR_HUMAN	Affects Binding	[15]
Adenosine receptor A1 (ADORA1)	OTI7X39E	AA1R_HUMAN	Affects Binding	[15]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Increases Expression	[14]
Bone morphogenetic protein receptor type-1A (BMPR1A)	OTQOA4ZH	BMR1A_HUMAN	Increases Expression	[14]
Tumor necrosis factor ligand superfamily member 6 (FASLG)	OTZARCHH	TNFL6_HUMAN	Increases Expression	[16]
Transforming growth factor beta-2 proprotein (TGFB2)	OTC0TXEP	TGFB2_HUMAN	Increases Expression	[14]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[17]
FAS-associated death domain protein (FADD)	OTV7GFHH	FADD_HUMAN	Decreases Expression	[13]
Frizzled-5 (FZD5)	OTXFFY56	FZD5_HUMAN	Increases Expression	[14]
Baculoviral IAP repeat-containing protein 3 (BIRC3)	OT3E95KB	BIRC3_HUMAN	Decreases Expression	[17]
Baculoviral IAP repeat-containing protein 2 (BIRC2)	OTFXFREP	BIRC2_HUMAN	Decreases Expression	[17]
Frizzled-3 (FZD3)	OTIWDN78	FZD3_HUMAN	Increases Expression	[14]
Diablo IAP-binding mitochondrial protein (DIABLO)	OTHJ9MCZ	DBLOH_HUMAN	Increases Expression	[17]
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A)	OTHCDQ22	PRGC1_HUMAN	Increases Expression	[18]
Lymphoid enhancer-binding factor 1 (LEF1)	OTWS5I5H	LEF1_HUMAN	Increases Expression	[14]
Mitogen-activated protein kinase 11 (MAPK11)	OT0AS010	MK11_HUMAN	Increases ADR	[19]
Tyrosine-protein phosphatase non-receptor type 12 (PTPN12)	OT5WA666	PTN12_HUMAN	Increases ADR	[19]
Sodium/nucleoside cotransporter 2 (SLC28A2)	OTFYZK8R	S28A2_HUMAN	Increases Transport	[20]
Equilibrative nucleoside transporter 3 (SLC29A3)	OTGLX8XU	S29A3_HUMAN	Affects Transport	[21]
Equilibrative nucleoside transporter 2 (SLC29A2)	OTUAOB8T	S29A2_HUMAN	Increases Uptake	[22]
Sodium/nucleoside cotransporter 1 (SLC28A1)	OTXWVV9O	S28A1_HUMAN	Affects Transport	[23]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Obesity	DCI75AC	N. A.	Phase 1	[24]

References

• [1] ClinicalTrials.gov (NCT03249272) Microvascular Dysfunction in Nonischemic Cardiomyopathy: Insights From CMR Assessment of Coronary Flow Reserve
• [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: 5596).
• [3] 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: 2844).
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] 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.
• [6] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [7] Role of MRP4 and MRP5 in biology and chemotherapy. AAPS PharmSci. 2002;4(3):E14.
• [8] Nitric oxide reduces adenosine transporter ENT1 gene (SLC29A1) promoter activity in human fetal endothelium from gestational diabetes. J Cell Physiol. 2006 Aug;208(2):451-60.
• [9] Regulation of sulfate assimilation in plants: 7. Cysteine inactivation of adenosine 5'-phosphosulfate sulfotransferase in Lemna minor L. Plant Physiol. 1978 Mar;61(3):342-7.
• [10] A functional genetic variation of adenosine deaminase affects the duration and intensity of deep sleep in humans. Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15676-81.
• [11] Functional role of the polymorphic 647 T/C variant of ENT1 (SLC29A1) and its association with alcohol withdrawal seizures. PLoS One. 2011 Jan 24;6(1):e16331. doi: 10.1371/journal.pone.0016331.
• [12] Adenosine downregulates DPPIV on HT-29 colon cancer cells by stimulating protein tyrosine phosphatase(s) and reducing ERK1/2 activity via a novel pathway. Am J Physiol Cell Physiol. 2006 Sep;291(3):C433-44.
• [13] 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.
• [14] Adenosine and Cordycepin Accelerate Tissue Remodeling Process through Adenosine Receptor Mediated Wnt/-Catenin Pathway Stimulation by Regulating GSK3b Activity. Int J Mol Sci. 2021 May 25;22(11):5571. doi: 10.3390/ijms22115571.
• [15] New 2,6,9-trisubstituted adenines as adenosine receptor antagonists: a preliminary SAR profile. Purinergic Signal. 2007 Sep;3(4):339-46. doi: 10.1007/s11302-007-9068-9. Epub 2007 Sep 19.
• [16] Apoptosis induced by nucleosides in the human hepatoma HepG2. World J Gastroenterol. 2005 Oct 28;11(40):6381-4. doi: 10.3748/wjg.v11.i40.6381.
• [17] Adenosine-induced caspase-3 activation by tuning Bcl-XL/DIABLO/IAP expression in HuH-7 human hepatoma cells. Cell Biol Toxicol. 2010 Aug;26(4):319-30. doi: 10.1007/s10565-009-9145-7. Epub 2010 Jan 9.
• [18] A cardiac-specific robotized cellular assay identified families of human ligands as inducers of PGC-1 expression and mitochondrial biogenesis. PLoS One. 2012;7(10):e46753. doi: 10.1371/journal.pone.0046753. Epub 2012 Oct 3.
• [19] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [20] Molecular cloning, functional expression and chromosomal localization of a cDNA encoding a human Na+/nucleoside cotransporter (hCNT2) selective for purine nucleosides and uridine. Mol Membr Biol. 1998 Oct-Dec;15(4):203-11. doi: 10.3109/09687689709044322.
• [21] Facilitated mitochondrial import of antiviral and anticancer nucleoside drugs by human equilibrative nucleoside transporter-3. Am J Physiol Gastrointest Liver Physiol. 2009 Apr;296(4):G910-22. doi: 10.1152/ajpgi.90672.2008. Epub 2009 Jan 22.
• [22] Molecular cloning and characterization of a nitrobenzylthioinosine-insensitive (ei) equilibrative nucleoside transporter from human placenta. Biochem J. 1997 Dec 15;328 ( Pt 3)(Pt 3):739-43. doi: 10.1042/bj3280739.
• [23] Molecular cloning and functional expression of cDNAs encoding a human Na+-nucleoside cotransporter (hCNT1). Am J Physiol. 1997 Feb;272(2 Pt 1):C707-14. doi: 10.1152/ajpcell.1997.272.2.C707.
• [24] ClinicalTrials.gov (NCT00859833) Effects of Body Mass Index on the Hyperemic Response to Regadenoson