Details of the Drug Combination

General Information of Drug Combination (ID: DCUO9M9)

• Drug Combination Name: Ruxolitinib + Vandetanib
• Indication: Invasive ductal carcinoma; Status: Investigative [1]
• Component Drugs:
  Ruxolitinib (DM7Q98D): Small molecular drug
  Vandetanib (DMRICNP): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: HS 578T
  Zero Interaction Potency (ZIP) Score: 7.6
  Bliss Independence Score: 7.92
  Loewe Additivity Score: 0.94
  LHighest Single Agent (HSA) Score: 0.25

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	[9]
Janus kinase 1 (JAK-1)	TT6DM01	JAK1_HUMAN	Modulator	[9]
Urokinase plasminogen activator surface receptor (PLAUR)	TTPRL03	UPAR_HUMAN	Inhibitor	[10]
HUMAN janus kinase 1 (JAK-1)	TTWKB01	JAK1_HUMAN	Inhibitor	[11]
HUMAN janus kinase 2 (JAK-2)	TT0F5HE	JAK2_HUMAN	Inhibitor	[11]

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	[12]

Indication(s) of Vandetanib

Disease Entry	ICD 11	Status	REF
Solid tumour/cancer	2A00-2F9Z	Approved	[8]

Vandetanib Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Epidermal growth factor receptor (EGFR)	TTGKNB4	EGFR_HUMAN	Inhibitor	[13]
Proto-oncogene c-Ret (RET)	TT4DXQT	RET_HUMAN	Inhibitor	[13]
Vascular endothelial growth factor receptor 2 (KDR)	TTUTJGQ	VGFR2_HUMAN	Inhibitor	[13]

Vandetanib 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	[14]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[15]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[15]

Vandetanib Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[16]

Vandetanib Interacts with 22 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2)	OTKOZRZP	PLOD2_HUMAN	Increases Expression	[17]
Stearoyl-CoA desaturase (SCD)	OTB1073G	SCD_HUMAN	Increases Expression	[17]
Insulin-induced gene 1 protein (INSIG1)	OTZF5X1D	INSI1_HUMAN	Increases Expression	[17]
BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like (BNIP3L)	OTJKOMXE	BNI3L_HUMAN	Increases Expression	[17]
Protein FAM13A (FAM13A)	OTZ6GN0Q	FA13A_HUMAN	Increases Expression	[17]
Phosphoglycerate kinase 1 (PGK1)	OT6V1ICH	PGK1_HUMAN	Increases Expression	[17]
Calbindin (CALB1)	OTM7IXDG	CALB1_HUMAN	Increases Expression	[17]
Prothymosin alpha (PTMA)	OT2W4T1M	PTMA_HUMAN	Decreases Expression	[17]
Trypsin-2 (PRSS2)	OTOMVUWL	TRY2_HUMAN	Increases Expression	[17]
Gamma-enolase (ENO2)	OTRODL0T	ENOG_HUMAN	Increases Expression	[17]
Solute carrier family 2, facilitated glucose transporter member 3 (SLC2A3)	OT2HZK5M	GTR3_HUMAN	Increases Expression	[17]
Histone H1.2 (H1-2)	OT0AVI4M	H12_HUMAN	Increases Expression	[17]
DNA mismatch repair protein Msh3 (MSH3)	OTD3YPVL	MSH3_HUMAN	Decreases Expression	[17]
Pro-adrenomedullin (ADM)	OT7T0TA4	ADML_HUMAN	Increases Expression	[17]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Decreases Phosphorylation	[18]
Collagen alpha-3(IV) chain (COL4A3)	OT6SB8X5	CO4A3_HUMAN	Increases Expression	[17]
Solute carrier family 2, facilitated glucose transporter member 14 (SLC2A14)	OTBFIOVY	GTR14_HUMAN	Increases Expression	[17]
Protein NDRG1 (NDRG1)	OTVO66BO	NDRG1_HUMAN	Increases Expression	[17]
TSC22 domain family protein 3 (TSC22D3)	OT03UM03	T22D3_HUMAN	Increases Expression	[17]
Transcription factor SOX-17 (SOX17)	OT9H4WWE	SOX17_HUMAN	Decreases Localization	[19]
Hypoxia-inducible lipid droplet-associated protein (HILPDA)	OTEID3ZM	HLPDA_HUMAN	Increases Expression	[17]
Insulin-induced gene 2 protein (INSIG2)	OTX4VY51	INSI2_HUMAN	Increases Expression	[17]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Invasive ductal carcinoma	DCE0TXG	BT-549	Investigative	[1]
Amelanotic melanoma	DCAHA17	MDA-MB-435	Investigative	[20]
Cutaneous melanoma	DCU8JDM	SK-MEL-28	Investigative	[20]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1126165
• [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] 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: 5717).
• [9] 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
• [10] Urokinase-type plasminogen activator receptor signaling is critical in nasopharyngeal carcinoma cell growth and metastasis.Cell Cycle. 2014;13(12):1958-69.
• [11] 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.
• [12] 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.
• [13] A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr Top Med Chem. 2007;7(14):1408-22.
• [14] Tyrosine kinase inhibitors and multidrug resistance proteins: interactions and biological consequences. Cancer Chemother Pharmacol. 2010 Jan;65(2):335-46.
• [15] Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013 Mar 15;19(6):1458-66.
• [16] FDA label of Vandetanib. The 2020 official website of the U.S. Food and Drug Administration.
• [17] ZD6474 inhibits tumor growth and intraperitoneal dissemination in a highly metastatic orthotopic gastric cancer model. Int J Cancer. 2006 Jan 15;118(2):483-9. doi: 10.1002/ijc.21340.
• [18] Autophagy inhibition induces enhanced proapoptotic effects of ZD6474 in glioblastoma. Br J Cancer. 2013 Jul 9;109(1):164-71. doi: 10.1038/bjc.2013.306. Epub 2013 Jun 25.
• [19] A high-throughput screen for teratogens using human pluripotent stem cells. Toxicol Sci. 2014 Jan;137(1):76-90. doi: 10.1093/toxsci/kft239. Epub 2013 Oct 23.
• [20] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125976