General Information of Drug Combination (ID: DCAL3GW)

Drug Combination Name
Amonafide Thioguanine
Indication
Disease Entry Status REF
Adult acute myeloid leukemia Investigative [1]
Component Drugs Amonafide   DMAH59S Thioguanine   DM7NKEV
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL
High-throughput Screening Result Testing Cell Line: HL-60(TB)
Zero Interaction Potency (ZIP) Score: 11.4
Bliss Independence Score: 9.08
Loewe Additivity Score: 9.94
LHighest Single Agent (HSA) Score: 12.72

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
Indication(s) of Amonafide
Disease Entry ICD 11 Status REF
Breast cancer 2C60-2C65 Phase 3 [2]
Ovarian cancer 2C73 Phase 3 [2]
Prostate cancer 2C82.0 Phase 3 [2]
Indication(s) of Thioguanine
Disease Entry ICD 11 Status REF
Acute lymphocytic leukaemia 2B33.3 Approved [3]
Acute myelogenous leukaemia 2A41 Approved [4]
Acute myeloid leukaemia 2A60 Approved [5]
Middle East Respiratory Syndrome (MERS) 1D64 Preclinical [6]
Severe acute respiratory syndrome (SARS) 1D65 Preclinical [6]
Thioguanine Interacts with 3 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
MERS-CoV papain-like proteinase (PL-PRO) TTYJOLE R1AB_CVEMC (854-2740) Inhibitor [6]
Inosine-5'-monophosphate dehydrogenase (IMPDH) TTCAQMW NOUNIPROTAC Intercalator [7]
SARS-CoV papain-like proteinase (PL-PRO) TTRGHB2 R1AB_CVHSA (819-2740) Inhibitor [6]
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Thioguanine Interacts with 3 DTP Molecule(s)
DTP Name DTP ID UniProt ID Mode of Action REF
Breast cancer resistance protein (ABCG2) DTI7UX6 ABCG2_HUMAN Substrate [8]
Multidrug resistance-associated protein 4 (ABCC4) DTCSGPB MRP4_HUMAN Substrate [9]
Concentrative Na(+)-nucleoside cotransporter 3 (SLC28A3) DT4YL5R S28A3_HUMAN Substrate [10]
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Thioguanine Interacts with 2 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Thiopurine methyltransferase (TPMT) DEFQ8VO TPMT_HUMAN Metabolism [11]
Hypoxanthine phosphoribosyltransferase (HPRT1) DEVXTP5 HPRT_HUMAN Metabolism [12]
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Thioguanine Interacts with 11 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Thiopurine S-methyltransferase (TPMT) OTFOX70W TPMT_HUMAN Increases ADR [13]
Hypoxanthine-guanine phosphoribosyltransferase (HPRT1) OTOEEEXG HPRT_HUMAN Decreases Response To Substance [14]
Thiopurine S-methyltransferase (TPMT) OTFOX70W TPMT_HUMAN Increases ADR [15]
Inosine-5'-monophosphate dehydrogenase 2 (IMPDH2) OTPG0K7E IMDH2_HUMAN Increases Expression [16]
Cellular tumor antigen p53 (TP53) OTIE1VH3 P53_HUMAN Increases Activity [17]
Dystrophin (DMD) OTD21T5J DMD_HUMAN Increases Splicing [18]
Occludin (OCLN) OTSUTVWL OCLN_HUMAN Decreases Activity [19]
DNA mismatch repair protein Msh2 (MSH2) OT10H1AB MSH2_HUMAN Increases Response To Substance [20]
ATP-binding cassette sub-family C member 5 (ABCC5) OT34G4US MRP5_HUMAN Decreases Response To Substance [21]
Caspase-8 (CASP8) OTA8TVI8 CASP8_HUMAN Increases Response To Substance [17]
Baculoviral IAP repeat-containing protein 2 (BIRC2) OTFXFREP BIRC2_HUMAN Decreases Response To Substance [22]
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⏷ Show the Full List of 11 DOT(s)

Test Results of This Drug Combination in Other Disease Systems

Indication DrugCom ID Cell Line Status REF
Anaplastic large cell lymphoma DCF0SOI SR Investigative [1]
Astrocytoma DCZNX1J SNB-19 Investigative [1]
Clear cell renal cell carcinoma DCCFB1M 786-0 Investigative [1]
Glioma DC07G7Z SF-268 Investigative [1]
Glioma DCQE1A8 SF-539 Investigative [1]
High grade ovarian serous adenocarcinoma DCXKLGV OVCAR-8 Investigative [1]
Lung adenocarcinoma DCK63Z7 HOP-62 Investigative [1]
Mixed endometrioid and clear cell carcinoma DCNPQW0 IGROV1 Investigative [1]
Papillary renal cell carcinoma DCTNFE1 ACHN Investigative [1]
Breast adenocarcinoma DCY7DHJ MDA-MB-468 Investigative [23]
Carcinoma DC9HLSK RXF 393 Investigative [23]
Colon adenocarcinoma DCBPC48 COLO 205 Investigative [23]
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⏷ Show the Full List of 12 DrugCom(s)

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 ClinicalTrials.gov (NCT00715637) Phase III Randomized Study of Amonafide (AS1413) and Cytarabine Versus Daunorubicin and Cytarabine in Patients With Secondary Acute Myeloid Leukemia (AML)- the ACCEDEStudy. U.S. National Institutes of Health.
3 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
4 Thioguanine 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: 6845).
6 Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus. Antiviral Res. 2015 Mar;115:9-16.
7 Immune effector cells produce lethal DNA damage in cells treated with a thiopurine. Cancer Res. 2009 Mar 15;69(6):2393-9.
8 ABC transporters and their role in nucleoside and nucleotide drug resistance. Biochem Pharmacol. 2012 Apr 15;83(8):1073-83.
9 Multidrug resistance protein 4 (MRP4/ABCC4) mediates efflux of bimane-glutathione. Int J Biochem Cell Biol. 2004 Feb;36(2):247-57.
10 Involvement of the concentrative nucleoside transporter 3 and equilibrative nucleoside transporter 2 in the resistance of T-lymphoblastic cell lines to thiopurines. Biochem Biophys Res Commun. 2006 Apr 28;343(1):208-15.
11 Usefulness of thiopurine methyltransferase and thiopurine metabolite analysis in clinical practice in patients with inflammatory bowel diseases. Acta Gastroenterol Belg. 2010 Jul-Sep;73(3):331-5.
12 Qualitative and quantitative difference in mutation induction between carbon- and neon-ion beams in normal human cells. Biol Sci Space. 2003 Dec;17(4):302-6.
13 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.
14 CRISPR/Cas9-mediated gene knockout screens and target identification via whole-genome sequencing uncover host genes required for picornavirus infection. J Biol Chem. 2017 Jun 23;292(25):10664-10671. doi: 10.1074/jbc.M117.782425. Epub 2017 Apr 26.
15 Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther. 2011 Mar;89(3):387-91. doi: 10.1038/clpt.2010.320. Epub 2011 Jan 26.
16 Petit E, Langouet S, Akhdar H, Nicolas-Nicolaz C, Guillouzo A, Morel F. Differential toxic effects of azathioprine, 6-mercaptopurine and 6-thioguanine on human hepatocytes. Toxicol In Vitro. 2008;22(3):632-642. [PMID: 18222062]
17 Important role of caspase-8 for chemosensitivity of ALL cells. Clin Cancer Res. 2011 Dec 15;17(24):7605-13. doi: 10.1158/1078-0432.CCR-11-0513. Epub 2011 Oct 18.
18 The effect of 6-thioguanine on alternative splicing and antisense-mediated exon skipping treatment for duchenne muscular dystrophy. PLoS Curr. 2012 Dec 12;4:ecurrents.md.597d700f92eaa70de261ea0d91821377. doi: 10.1371/currents.md.597d700f92eaa70de261ea0d91821377.
19 The thiopurine methyltransferase genetic polymorphism is associated with thioguanine-related veno-occlusive disease of the liver in children with acute lymphoblastic leukemia. Clin Pharmacol Ther. 2006 Oct;80(4):375-83. doi: 10.1016/j.clpt.2006.07.002.
20 The effect of Msh2 knockdown on methylating agent induced toxicity in DNA glycosylase deficient cells. Toxicology. 2010 Jan 31;268(1-2):111-7. doi: 10.1016/j.tox.2009.12.008. Epub 2009 Dec 16.
21 The multidrug resistance protein 5 (ABCC5) confers resistance to 5-fluorouracil and transports its monophosphorylated metabolites. Mol Cancer Ther. 2005 May;4(5):855-63.
22 Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias. Clin Cancer Res. 2000 May;6(5):1796-803.
23 Biologically active neutrophil chemokine pattern in tonsillitis.Clin Exp Immunol. 2004 Mar;135(3):511-8. doi: 10.1111/j.1365-2249.2003.02390.x.