Details of the Drug Combination

General Information of Drug Combination (ID: DCODLS4)

• Drug Combination Name: Thioguanine + SCH 727965
• Indication: Pleural epithelioid mesothelioma; Status: Investigative [1]
• Component Drugs:
  Thioguanine (DM7NKEV): Small molecular drug
  SCH 727965 (DMCJLD1): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: NCI-H226
  Zero Interaction Potency (ZIP) Score: 4.76
  Bliss Independence Score: 6.62
  Loewe Additivity Score: 3.3
  LHighest Single Agent (HSA) Score: 3.94

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Thioguanine

Disease Entry	ICD 11	Status	REF
Acute lymphocytic leukaemia	2B33.3	Approved	[2]
Acute myelogenous leukaemia	2A41	Approved	[3]
Acute myeloid leukaemia	2A60	Approved	[4]
Middle East Respiratory Syndrome (MERS)	1D64	Preclinical	[5]
Severe acute respiratory syndrome (SARS)	1D65	Preclinical	[5]

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	[5]
Inosine-5'-monophosphate dehydrogenase (IMPDH)	TTCAQMW	NOUNIPROTAC	Intercalator	[7]
SARS-CoV papain-like proteinase (PL-PRO)	TTRGHB2	R1AB_CVHSA (819-2740)	Inhibitor	[5]

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]

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]

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]

Indication(s) of SCH 727965

Disease Entry	ICD 11	Status	REF
Acute lymphoblastic leukaemia	2A85	Discontinued in Phase 3	[6]

SCH 727965 Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Cyclin-dependent kinase 9 (CDK9)	TT1LVF2	CDK9_HUMAN	Inhibitor	[23]
Cyclin-dependent kinase 1 (CDK1)	TTH6V3D	CDK1_HUMAN	Inhibitor	[23]
Cyclin-dependent kinase 2 (CDK2)	TT7HF4W	CDK2_HUMAN	Inhibitor	[23]

SCH 727965 Interacts with 7 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Phosphorylation	[24]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[24]
Breast cancer type 1 susceptibility protein (BRCA1)	OT5BN6VH	BRCA1_HUMAN	Decreases Expression	[25]
Breast cancer type 2 susceptibility protein (BRCA2)	OTF1XSV1	BRCA2_HUMAN	Decreases Expression	[25]
DNA repair protein RAD51 homolog 1 (RAD51)	OTNVWGC1	RAD51_HUMAN	Decreases Expression	[25]
Fanconi anemia group D2 protein (FANCD2)	OTVEB5LF	FACD2_HUMAN	Decreases Expression	[25]
Cyclin-dependent kinase 12 (CDK12)	OTZUDGNU	CDK12_HUMAN	Decreases Activity	[25]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adult acute myeloid leukemia	DCPH6YF	HL-60(TB)	Investigative	[26]
Anaplastic large cell lymphoma	DCKITK8	SR	Investigative	[26]
Astrocytoma	DCPIJ2G	U251	Investigative	[26]
Astrocytoma	DCDHWEJ	SNB-19	Investigative	[26]
Childhood T acute lymphoblastic leukemia	DC8LGXH	CCRF-CEM	Investigative	[26]
Chronic myelogenous leukemia	DCY47EG	K-562	Investigative	[26]
Glioma	DCW6I6D	SF-295	Investigative	[26]
Adenocarcinoma	DCQJ74A	DU-145	Investigative	[1]
Adenocarcinoma	DCLV9NP	A549	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCHA01T	NCI\\/ADR-RES	Investigative	[1]

References

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• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] Thioguanine 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: 6845).
• [5] Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus. Antiviral Res. 2015 Mar;115:9-16.
• [6] 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: 7379).
• [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] Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
• [24] Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor. Mol Cancer Ther. 2010 Aug;9(8):2344-53. doi: 10.1158/1535-7163.MCT-10-0324. Epub 2010 Jul 27.
• [25] CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer. Cell Rep. 2016 Nov 22;17(9):2367-2381. doi: 10.1016/j.celrep.2016.10.077.
• [26] 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.