Details of the Drug Combination

General Information of Drug Combination (ID: DCH645M)

• Drug Combination Name: ABIRATERONE + Dexrazoxane
• Indication: Adenocarcinoma; Status: Investigative [1]
• Component Drugs:
  ABIRATERONE (DM8V75C): Small molecular drug
  Dexrazoxane (DMD7X1O): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: HCT-15
  Zero Interaction Potency (ZIP) Score: 8.24
  Bliss Independence Score: 11.78
  Loewe Additivity Score: 1.59
  LHighest Single Agent (HSA) Score: 11.56

Molecular Interaction Atlas of This Drug Combination

Indication(s) of ABIRATERONE

Disease Entry	ICD 11	Status	REF
Prostate cancer	2C82.0	Approved	[2]

ABIRATERONE Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Steroid 17-alpha-monooxygenase (S17AH)	TTRA5BZ	CP17A_HUMAN	Modulator	[7]

ABIRATERONE Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1)	OTZKVLVJ	CP17A_HUMAN	Decreases Activity	[8]
Tissue factor (F3)	OT3MSU3B	TF_HUMAN	Increases Expression	[9]
Membrane cofactor protein (CD46)	OTQ8NWJD	MCP_HUMAN	Increases Expression	[10]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Decreases Response To Substance	[11]

Indication(s) of Dexrazoxane

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Approved	[3]
Chemoprotection	N.A.	Approved	[4]
Inflammatory breast cancer	2C62	Approved	[5]
Respiratory tract disease	CB7Z	Investigative	[6]

Dexrazoxane Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
DNA topoisomerase II beta (TOP2B)	TT4NVEM	TOP2B_HUMAN	Inhibitor	[12]
DNA topoisomerase II (TOP2)	TT0IHXV	TOP2A_HUMAN; TOP2B_HUMAN	Modulator	[13]

Dexrazoxane Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Dihydropyrimidinase-related protein 1 (DRP1)	DE0EUXB	DPYL1_HUMAN	Metabolism	[14]

Dexrazoxane Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
DNA topoisomerase 2-alpha (TOP2A)	OT6LPS08	TOP2A_HUMAN	Decreases Activity	[15]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Glioma	DCMP8YH	SF-539	Investigative	[16]
Adenocarcinoma	DCK7QO9	HT29	Investigative	[1]

References

• [1] Loss of function mutations in VARS encoding cytoplasmic valyl-tRNA synthetase cause microcephaly, seizures, and progressive cerebral atrophy.Hum Genet. 2018 Apr;137(4):293-303. doi: 10.1007/s00439-018-1882-3. Epub 2018 Apr 24.
• [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: 6745).
• [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: 7330).
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] Dexrazoxane FDA Label
• [6] Design and development of antisense drugs. Expert Opin. Drug Discov. 2008 3(10):1189-1207.
• [7] 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
• [8] A fission yeast-based test system for the determination of IC50 values of anti-prostate tumor drugs acting on CYP21. J Enzyme Inhib Med Chem. 2006 Oct;21(5):547-56.
• [9] Elucidating mechanisms of toxicity using phenotypic data from primary human cell systems--a chemical biology approach for thrombosis-related side effects. Int J Mol Sci. 2015 Jan 5;16(1):1008-29. doi: 10.3390/ijms16011008.
• [10] Targeting CD46 for both adenocarcinoma and neuroendocrine prostate cancer. JCI Insight. 2018 Sep 6;3(17):e121497. doi: 10.1172/jci.insight.121497. eCollection 2018 Sep 6.
• [11] Targeting chromatin binding regulation of constitutively active AR variants to overcome prostate cancer resistance to endocrine-based therapies. Nucleic Acids Res. 2015 Jul 13;43(12):5880-97. doi: 10.1093/nar/gkv262. Epub 2015 Apr 23.
• [12] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [13] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [14] Metabolism of the cardioprotective drug dexrazoxane and one of its metabolites by isolated rat myocytes, hepatocytes, and blood. Drug Metab Dispos. 2005 Jun;33(6):719-25.
• [15] Investigation of novel dexrazoxane analogue JR-311 shows significant cardioprotective effects through topoisomerase IIbeta but not its iron chelating metabolite. Toxicology. 2017 Dec 1;392:1-10. doi: 10.1016/j.tox.2017.09.012. Epub 2017 Sep 21.
• [16] 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.