Details of the Drug Combination

General Information of Drug Combination (ID: DCU5MEN)

• Drug Combination Name: Ruxolitinib + Thioguanine
• Indication: Malignant melanoma; Status: Investigative [1]
• Component Drugs:
  Ruxolitinib (DM7Q98D): Small molecular drug
  Thioguanine (DM7NKEV): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: LOX IMVI
  Zero Interaction Potency (ZIP) Score: 0.48
  Bliss Independence Score: 2.9
  Loewe Additivity Score: 0.48
  LHighest Single Agent (HSA) Score: 6.2

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Ruxolitinib

Disease Entry	ICD 11	Status	REF
Essential thrombocythemia	3B63.1Z	Approved	[2]
High-risk myelofibrosis	2A20.2	Approved	[3]
Myelofibrosis	2A22	Approved	[4]
Myeloproliferative neoplasm	2A20	Approved	[5]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[6]
Pancreatic cancer	2C10	Phase 3	[3]
Atopic dermatitis	EA80	Phase 1/2	[7]
Vitiligo	ED63.0	Phase 1/2	[7]

Ruxolitinib Interacts with 5 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Janus kinase 2 (JAK-2)	TTRMX3V	JAK2_HUMAN	Modulator	[11]
Janus kinase 1 (JAK-1)	TT6DM01	JAK1_HUMAN	Modulator	[11]
Urokinase plasminogen activator surface receptor (PLAUR)	TTPRL03	UPAR_HUMAN	Inhibitor	[12]
HUMAN janus kinase 1 (JAK-1)	TTWKB01	JAK1_HUMAN	Inhibitor	[13]
HUMAN janus kinase 2 (JAK-2)	TT0F5HE	JAK2_HUMAN	Inhibitor	[13]

Ruxolitinib Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Mitogen-activated protein kinase 14 (MAPK14)	OT5TCO3O	MK14_HUMAN	Increases ADR	[14]

Indication(s) of Thioguanine

Disease Entry	ICD 11	Status	REF
Acute lymphocytic leukaemia	2B33.3	Approved	[4]
Acute myelogenous leukaemia	2A41	Approved	[8]
Acute myeloid leukaemia	2A60	Approved	[9]
Middle East Respiratory Syndrome (MERS)	1D64	Preclinical	[10]
Severe acute respiratory syndrome (SARS)	1D65	Preclinical	[10]

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	[10]
Inosine-5'-monophosphate dehydrogenase (IMPDH)	TTCAQMW	NOUNIPROTAC	Intercalator	[15]
SARS-CoV papain-like proteinase (PL-PRO)	TTRGHB2	R1AB_CVHSA (819-2740)	Inhibitor	[10]

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	[16]
Multidrug resistance-associated protein 4 (ABCC4)	DTCSGPB	MRP4_HUMAN	Substrate	[17]
Concentrative Na(+)-nucleoside cotransporter 3 (SLC28A3)	DT4YL5R	S28A3_HUMAN	Substrate	[18]

Thioguanine Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Thiopurine methyltransferase (TPMT)	DEFQ8VO	TPMT_HUMAN	Metabolism	[19]
Hypoxanthine phosphoribosyltransferase (HPRT1)	DEVXTP5	HPRT_HUMAN	Metabolism	[20]

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	[14]
Hypoxanthine-guanine phosphoribosyltransferase (HPRT1)	OTOEEEXG	HPRT_HUMAN	Decreases Response To Substance	[21]
Thiopurine S-methyltransferase (TPMT)	OTFOX70W	TPMT_HUMAN	Increases ADR	[22]
Inosine-5'-monophosphate dehydrogenase 2 (IMPDH2)	OTPG0K7E	IMDH2_HUMAN	Increases Expression	[23]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Activity	[24]
Dystrophin (DMD)	OTD21T5J	DMD_HUMAN	Increases Splicing	[25]
Occludin (OCLN)	OTSUTVWL	OCLN_HUMAN	Decreases Activity	[26]
DNA mismatch repair protein Msh2 (MSH2)	OT10H1AB	MSH2_HUMAN	Increases Response To Substance	[27]
ATP-binding cassette sub-family C member 5 (ABCC5)	OT34G4US	MRP5_HUMAN	Decreases Response To Substance	[28]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Response To Substance	[24]
Baculoviral IAP repeat-containing protein 2 (BIRC2)	OTFXFREP	BIRC2_HUMAN	Decreases Response To Substance	[29]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adult T acute lymphoblastic leukemia	DCQLJ3S	MOLT-4	Investigative	[30]
Astrocytoma	DC0UB9C	SNB-19	Investigative	[30]
Chronic myelogenous leukemia	DCIMAZ1	K-562	Investigative	[30]
Clear cell renal cell carcinoma	DCWRIIN	786-0	Investigative	[30]
Clear cell renal cell carcinoma	DC4O4IJ	CAKI-1	Investigative	[30]
Glioma	DCDD9GJ	SF-295	Investigative	[30]
Papillary renal cell carcinoma	DC62QJ5	ACHN	Investigative	[30]
Renal cell carcinoma	DCPOKV3	SN12C	Investigative	[30]
Breast adenocarcinoma	DCIK0CV	MDA-MB-468	Investigative	[31]
Invasive ductal carcinoma	DCT9FT6	HS 578T	Investigative	[31]
Adenocarcinoma	DCI2HA0	DU-145	Investigative	[1]
Lung adenocarcinoma	DCSWOC4	EKVX	Investigative	[1]
Ovarian serous cystadenocarcinoma	DCWCZMJ	SK-OV-3	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] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [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: 5688).
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] Ruxolitinib FDA Label
• [6] Incyte begins Phase III trial of ruxolitinib to treat Covid-19. 20.April.2020.
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] Thioguanine FDA Label
• [9] 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).
• [10] Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus. Antiviral Res. 2015 Mar;115:9-16.
• [11] 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
• [12] Urokinase-type plasminogen activator receptor signaling is critical in nasopharyngeal carcinoma cell growth and metastasis.Cell Cycle. 2014;13(12):1958-69.
• [13] The Use of Anti-Inflammatory Drugs in the Treatment of People With Severe Coronavirus Disease 2019 (COVID-19): The Perspectives of Clinical Immunologists From China. Clin Immunol. 2020 May;214:108393.
• [14] 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.
• [15] Immune effector cells produce lethal DNA damage in cells treated with a thiopurine. Cancer Res. 2009 Mar 15;69(6):2393-9.
• [16] ABC transporters and their role in nucleoside and nucleotide drug resistance. Biochem Pharmacol. 2012 Apr 15;83(8):1073-83.
• [17] Multidrug resistance protein 4 (MRP4/ABCC4) mediates efflux of bimane-glutathione. Int J Biochem Cell Biol. 2004 Feb;36(2):247-57.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] 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]
• [24] 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.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias. Clin Cancer Res. 2000 May;6(5):1796-803.
• [30] 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.
• [31] 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.