Details of the Drug Combination

General Information of Drug Combination (ID: DCEEPMU)

• Drug Combination Name: CGS 21680 + Idarubicin
• Indication: Glioblastoma?; Status: Investigative [1]
• Component Drugs:
  CGS 21680 (DMZ0TGY): Small molecular drug
  Idarubicin (DMM0XGL): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: T98G
  Zero Interaction Potency (ZIP) Score: 25.22
  Bliss Independence Score: 25.22
  Loewe Additivity Score: 13.03
  LHighest Single Agent (HSA) Score: 13.03

Molecular Interaction Atlas of This Drug Combination

Indication(s) of CGS 21680

Disease Entry	ICD 11	Status	REF
Discovery agent	N.A.	Investigative	[2]

CGS 21680 Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adenosine A2a receptor (ADORA2A)	TTM2AOE	AA2AR_HUMAN	Agonist	[6]
Adenosine A2b receptor (ADORA2B)	TTNE7KG	AA2BR_HUMAN	Agonist	[7]

CGS 21680 Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Basic helix-loop-helix ARNT-like protein 1 (BMAL1)	OTMI12L2	BMAL1_HUMAN	Increases Expression	[8]
Period circadian protein homolog 2 (PER2)	OTU2B1DJ	PER2_HUMAN	Decreases Expression	[8]
Circadian locomoter output cycles protein kaput (CLOCK)	OTNEOJY7	CLOCK_HUMAN	Increases Expression	[8]
Collagen alpha-1(III) chain (COL3A1)	OTT1EMLM	CO3A1_HUMAN	Increases Expression	[9]
72 kDa type IV collagenase (MMP2)	OT5NIWA2	MMP2_HUMAN	Decreases Activity	[10]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Decreases Expression	[10]
Nuclear receptor subfamily 1 group D member 1 (NR1D1)	OTJ38PTB	NR1D1_HUMAN	Increases Expression	[8]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Affects Localization	[9]
Matrix metalloproteinase-14 (MMP14)	OT9C197Z	MMP14_HUMAN	Decreases Activity	[10]

Indication(s) of Idarubicin

Disease Entry	ICD 11	Status	REF
Acute myelogenous leukaemia	2A41	Approved	[3]
Acute myeloid leukaemia	2A60	Approved	[4]
Adult acute monocytic leukemia	N.A.	Approved	[3]
Childhood acute megakaryoblastic leukemia	N.A.	Approved	[3]
Leukemia	N.A.	Approved	[3]

Idarubicin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
DNA topoisomerase II (TOP2)	TT0IHXV	TOP2A_HUMAN; TOP2B_HUMAN	Modulator	[12]

Idarubicin Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 1 (ABCC1)	DTSYQGK	MRP1_HUMAN	Substrate	[13]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[14]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[14]

Idarubicin Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[15]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[15]

Idarubicin Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Estrogen receptor (ESR1)	OTKLU61J	ESR1_HUMAN	Decreases Activity	[11]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[16]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Increases Activity	[11]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Increases Expression	[17]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Decreases Activity	[11]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[18]
Peroxisome proliferator-activated receptor delta (PPARD)	OTI4WTOP	PPARD_HUMAN	Decreases Activity	[11]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[19]
Bile acid receptor (NR1H4)	OTWZLPTB	NR1H4_HUMAN	Decreases Activity	[11]

References

• [1] Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
• [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: 424).
• [3] Idarubicin 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: 7083).
• [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] Effects of CGS 21680, a selective adenosine A2A receptor agonist, on allergic airways inflammation in the rat. Eur J Pharmacol. 2002 Mar 8;438(3):183-8.
• [7] [3H]CGS 21680, a selective A2 adenosine receptor agonist directly labels A2 receptors in rat brain. J Pharmacol Exp Ther. 1989 Dec;251(3):888-93.
• [8] Adenosine A2A receptor and TNF- regulate the circadian machinery of the human monocytic THP-1 cells. Inflammation. 2013 Feb;36(1):152-62. doi: 10.1007/s10753-012-9530-x.
• [9] Adenosine A(2A) receptor promotes collagen type III synthesis via -catenin activation in human dermal fibroblasts. Br J Pharmacol. 2016 Dec;173(23):3279-3291. doi: 10.1111/bph.13615. Epub 2016 Oct 4.
• [10] Adenosine A(2A) receptors play a role in the pathogenesis of hepatic cirrhosis. Br J Pharmacol. 2006 Aug;148(8):1144-55. doi: 10.1038/sj.bjp.0706812. Epub 2006 Jun 19.
• [11] Quantitative high-throughput profiling of environmental chemicals and drugs that modulate farnesoid X receptor. Sci Rep. 2014 Sep 26;4:6437. doi: 10.1038/srep06437.
• [12] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [13] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [14] Amonafide L-malate is not a substrate for multidrug resistance proteins in secondary acute myeloid leukemia. Leukemia. 2008 Nov;22(11):2110-5.
• [15] In vitro evaluation of cytochrome P450-mediated drug interactions between cytarabine, idarubicin, itraconazole and caspofungin. Hematology. 2004 Jun;9(3):217-21.
• [16] A Quantitative Approach to Screen for Nephrotoxic Compounds In Vitro. J Am Soc Nephrol. 2016 Apr;27(4):1015-28. doi: 10.1681/ASN.2015010060. Epub 2015 Aug 10.
• [17] The use of biochemical markers in cardiotoxicity monitoring in patients treated for leukemia. Neoplasma. 2005;52(5):430-4.
• [18] The induction of apoptosis by daunorubicin and idarubicin in human trisomic and diabetic fibroblasts. Cell Mol Biol Lett. 2008;13(2):182-94. doi: 10.2478/s11658-007-0045-7. Epub 2008 Apr 10.
• [19] Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model. Toxicol Sci. 2013 Dec;136(2):581-94. doi: 10.1093/toxsci/kft205. Epub 2013 Sep 19.