Details of the Drug Combination

General Information of Drug Combination (ID: DCJG2ET)

• Drug Combination Name: Ruxolitinib + Fludarabine
• Indication: Clear cell renal cell carcinoma; Status: Investigative [1]
• Component Drugs:
  Ruxolitinib (DM7Q98D): Small molecular drug
  Fludarabine (DMVRLT7): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: 786-0
  Zero Interaction Potency (ZIP) Score: 3.46
  Bliss Independence Score: 5.11
  Loewe Additivity Score: 1.24
  LHighest Single Agent (HSA) Score: 6.47

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	[10]
Janus kinase 1 (JAK-1)	TT6DM01	JAK1_HUMAN	Modulator	[10]
Urokinase plasminogen activator surface receptor (PLAUR)	TTPRL03	UPAR_HUMAN	Inhibitor	[11]
HUMAN janus kinase 1 (JAK-1)	TTWKB01	JAK1_HUMAN	Inhibitor	[12]
HUMAN janus kinase 2 (JAK-2)	TT0F5HE	JAK2_HUMAN	Inhibitor	[12]

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	[13]

Indication(s) of Fludarabine

Disease Entry	ICD 11	Status	REF
Acute myelogenous leukaemia	2A41	Approved	[8]
Cutaneous melanoma	2C30	Approved	[8]
Haematological malignancy	2B33.Y	Approved	[9]
Hematologic disease	3C0Z	Approved	[8]
Hepatosplenic T-cell lymphoma	N.A.	Approved	[8]
Immunodeficiency	4A00-4A85	Approved	[8]
Large granular lymphocytic leukemia	2A90.1	Approved	[8]
Lung cancer	2C25.0	Approved	[8]
MALT lymphoma	N.A.	Approved	[8]
Multiple sclerosis	8A40	Approved	[8]
Myeloproliferative neoplasm	2A20	Approved	[8]
Nodal marginal zone lymphoma	2A85.0	Approved	[8]
Primary cutaneous peripheral T-cell lymphoma not otherwise specified	N.A.	Approved	[8]
Recurrent adult burkitt lymphoma	2A85.6	Approved	[8]
Small intestine lymphoma	N.A.	Approved	[8]
Splenic marginal zone lymphoma	N.A.	Approved	[8]
Systemic lupus erythematosus	4A40.0	Approved	[8]
Systemic sclerosis	4A42	Approved	[8]
Testicular lymphoma	N.A.	Approved	[8]
Classic Hodgkin lymphoma	N.A.	Investigative	[8]
Colon cancer	2B90.Z	Investigative	[8]
Gastric cancer	2B72	Investigative	[8]
Neuroblastoma	2D11.2	Investigative	[8]

Fludarabine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adenosine deaminase (ADA)	TTLP57V	ADA_HUMAN	Inhibitor	[17]

Fludarabine Interacts with 22 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Tumor necrosis factor receptor superfamily member 10A (TNFRSF10A)	OTBPCU2O	TR10A_HUMAN	Affects Expression	[18]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[19]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[19]
Proliferating cell nuclear antigen (PCNA)	OTHZ1RIA	PCNA_HUMAN	Increases Expression	[20]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Increases Expression	[21]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Expression	[14]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[22]
DNA cytosine-5)-methyltransferase 1 (DNMT1)	OTM2DGTK	DNMT1_HUMAN	Decreases Expression	[23]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[15]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[15]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Increases Activity	[24]
Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2)	OTUE7Z91	MP2K2_HUMAN	Increases Activity	[24]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[20]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[22]
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN)	OTOWDUNT	PTEN_HUMAN	Increases Expression	[23]
Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1)	OT4Y9NQI	MP2K1_HUMAN	Increases Activity	[24]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[21]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[21]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[22]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Decreases Expression	[15]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Increases Expression	[16]
Growth/differentiation factor 15 (GDF15)	OTWQN50N	GDF15_HUMAN	Increases Expression	[20]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Colon carcinoma	DCFT49J	KM12	Investigative	[25]
Adenocarcinoma	DCJ554J	DU-145	Investigative	[26]

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] 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] Fludarabine 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: 4802).
• [10] 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
• [11] Urokinase-type plasminogen activator receptor signaling is critical in nasopharyngeal carcinoma cell growth and metastasis.Cell Cycle. 2014;13(12):1958-69.
• [12] 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.
• [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] Role of histone deacetylase inhibitor-induced reactive oxygen species and DNA damage in LAQ-824/fludarabine antileukemic interactions. Mol Cancer Ther. 2008 Oct;7(10):3285-97. doi: 10.1158/1535-7163.MCT-08-0385.
• [15] 9-beta-D-arabinofuranosyl-2-fluoroadenine inhibits expression of vascular endothelial growth factor through hypoxia-inducible factor-1 in human ovarian cancer cells. Mol Pharmacol. 2004 Jul;66(1):178-86. doi: 10.1124/mol.66.1.178.
• [16] MDM2 antagonists activate p53 and synergize with genotoxic drugs in B-cell chronic lymphocytic leukemia cells. Blood. 2006 May 15;107(10):4109-14. doi: 10.1182/blood-2005-08-3273. Epub 2006 Jan 26.
• [17] Purine nucleoside analogs in indolent non-Hodgkin's lymphoma. Oncology (Williston Park). 2000 Jun;14(6 Suppl 2):13-5.
• [18] Role of the TRAIL/APO2-L death receptors in chlorambucil- and fludarabine-induced apoptosis in chronic lymphocytic leukemia. Oncogene. 2003 Nov 13;22(51):8356-69. doi: 10.1038/sj.onc.1207004.
• [19] Differential effects of chemotherapeutic drugs versus the MDM-2 antagonist nutlin-3 on cell cycle progression and induction of apoptosis in SKW6.4 lymphoblastoid B-cells. J Cell Biochem. 2008 May 15;104(2):595-605. doi: 10.1002/jcb.21649.
• [20] Functional integrity of the p53-mediated apoptotic pathway induced by the nongenotoxic agent nutlin-3 in B-cell chronic lymphocytic leukemia (B-CLL). Blood. 2006 May 15;107(10):4122-9. doi: 10.1182/blood-2005-11-4465. Epub 2006 Jan 26.
• [21] Matrix metalloproteinase-9 is involved in chronic lymphocytic leukemia cell response to fludarabine and arsenic trioxide. PLoS One. 2014 Jun 23;9(6):e99993. doi: 10.1371/journal.pone.0099993. eCollection 2014.
• [22] Caspase 8 activation independent of Fas (CD95/APO-1) signaling may mediate killing of B-chronic lymphocytic leukemia cells by cytotoxic drugs or gamma radiation. Blood. 2001 Nov 1;98(9):2800-7. doi: 10.1182/blood.v98.9.2800.
• [23] Comparative effects of retinoic acid, vitamin D and resveratrol alone and in combination with adenosine analogues on methylation and expression of phosphatase and tensin homologue tumour suppressor gene in breast cancer cells. Br J Nutr. 2012 Mar;107(6):781-90. doi: 10.1017/S0007114511003631. Epub 2011 Aug 1.
• [24] The histone deacetylase inhibitor MS-275 interacts synergistically with fludarabine to induce apoptosis in human leukemia cells. Cancer Res. 2004 Apr 1;64(7):2590-600. doi: 10.1158/0008-5472.can-03-2631.
• [25] 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.
• [26] 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.