Details of the Drug Combination

General Information of Drug Combination (ID: DCYWALF)

• Drug Combination Name: Vandetanib + Plicamycin
• Indication: Melanoma; Status: Investigative [1]
• Component Drugs:
  Vandetanib (DMRICNP): Small molecular drug
  Plicamycin (DM7C8YV): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: MALME-3M
  Zero Interaction Potency (ZIP) Score: 2.79
  Bliss Independence Score: 5.09
  Loewe Additivity Score: 4.19
  LHighest Single Agent (HSA) Score: 4.38

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Vandetanib

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

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	[6]
Proto-oncogene c-Ret (RET)	TT4DXQT	RET_HUMAN	Inhibitor	[6]
Vascular endothelial growth factor receptor 2 (KDR)	TTUTJGQ	VGFR2_HUMAN	Inhibitor	[6]

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	[7]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[8]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[8]

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	[9]

Vandetanib Interacts with 34 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Proto-oncogene tyrosine-protein kinase receptor Ret (RET)	OTLU040A	RET_HUMAN	Decreases Phosphorylation	[10]
Procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2)	OTKOZRZP	PLOD2_HUMAN	Increases Expression	[11]
Stearoyl-CoA desaturase (SCD)	OTB1073G	SCD_HUMAN	Increases Expression	[11]
Insulin-induced gene 1 protein (INSIG1)	OTZF5X1D	INSI1_HUMAN	Increases Expression	[11]
BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like (BNIP3L)	OTJKOMXE	BNI3L_HUMAN	Increases Expression	[11]
Protein FAM13A (FAM13A)	OTZ6GN0Q	FA13A_HUMAN	Increases Expression	[11]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Decreases Activity	[12]
Phosphoglycerate kinase 1 (PGK1)	OT6V1ICH	PGK1_HUMAN	Increases Expression	[11]
Calbindin (CALB1)	OTM7IXDG	CALB1_HUMAN	Increases Expression	[11]
Prothymosin alpha (PTMA)	OT2W4T1M	PTMA_HUMAN	Decreases Expression	[11]
Trypsin-2 (PRSS2)	OTOMVUWL	TRY2_HUMAN	Increases Expression	[11]
Insulin-like growth factor-binding protein 1 (IGFBP1)	OT6UQV2K	IBP1_HUMAN	Increases Expression	[11]
Gamma-enolase (ENO2)	OTRODL0T	ENOG_HUMAN	Increases Expression	[11]
Solute carrier family 2, facilitated glucose transporter member 3 (SLC2A3)	OT2HZK5M	GTR3_HUMAN	Increases Expression	[11]
Mucin-1 (MUC1)	OTHQI7IY	MUC1_HUMAN	Increases Expression	[11]
Histone H1.2 (H1-2)	OT0AVI4M	H12_HUMAN	Increases Expression	[11]
Insulin-like growth factor-binding protein 3 (IGFBP3)	OTIX63TX	IBP3_HUMAN	Increases Expression	[11]
DNA mismatch repair protein Msh3 (MSH3)	OTD3YPVL	MSH3_HUMAN	Decreases Expression	[11]
Alanine aminotransferase 1 (GPT)	OTOXOA0Q	ALAT1_HUMAN	Increases Secretion	[13]
Dual specificity protein phosphatase 1 (DUSP1)	OTN6BR75	DUS1_HUMAN	Increases Expression	[11]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Phosphorylation	[14]
Pro-adrenomedullin (ADM)	OT7T0TA4	ADML_HUMAN	Increases Expression	[11]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Decreases Phosphorylation	[14]
Collagen alpha-3(IV) chain (COL4A3)	OT6SB8X5	CO4A3_HUMAN	Increases Expression	[11]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Expression	[15]
Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1)	OTHBQVD5	4EBP1_HUMAN	Decreases Phosphorylation	[14]
Solute carrier family 2, facilitated glucose transporter member 14 (SLC2A14)	OTBFIOVY	GTR14_HUMAN	Increases Expression	[11]
Protein NDRG1 (NDRG1)	OTVO66BO	NDRG1_HUMAN	Increases Expression	[11]
TSC22 domain family protein 3 (TSC22D3)	OT03UM03	T22D3_HUMAN	Increases Expression	[11]
Angiopoietin-related protein 4 (ANGPTL4)	OTQL5SPX	ANGL4_HUMAN	Increases Expression	[11]
Transcription factor SOX-17 (SOX17)	OT9H4WWE	SOX17_HUMAN	Decreases Localization	[16]
Lysine-specific demethylase 3A (KDM3A)	OTZYJ8VN	KDM3A_HUMAN	Increases Expression	[11]
Hypoxia-inducible lipid droplet-associated protein (HILPDA)	OTEID3ZM	HLPDA_HUMAN	Increases Expression	[11]
Insulin-induced gene 2 protein (INSIG2)	OTX4VY51	INSI2_HUMAN	Increases Expression	[11]

Indication(s) of Plicamycin

Disease Entry	ICD 11	Status	REF
Hypercalcaemia	5B91.0	Approved	[3]
Testicular cancer	2C80	Approved	[3]
Solid tumour/cancer	2A00-2F9Z	Withdrawn from market	[4]
Lung cancer	2C25.0	Investigative	[5]
Ovarian cancer	2C73	Investigative	[5]

Plicamycin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
RNA synthesis (hRNA synth)	TTX2AYW	NOUNIPROTAC	Modulator	[18]

Plicamycin Interacts with 16 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
17-beta-hydroxysteroid dehydrogenase type 2 (HSD17B2)	OT3K7HY5	DHB2_HUMAN	Decreases Expression	[19]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Expression	[20]
Aryl hydrocarbon receptor (AHR)	OTFE4EYE	AHR_HUMAN	Decreases Expression	[20]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Expression	[20]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[21]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Activity	[21]
Epoxide hydrolase 1 (EPHX1)	OTBKWQER	HYEP_HUMAN	Decreases Expression	[22]
Transcription factor Sp1 (SP1)	OTISPT4X	SP1_HUMAN	Decreases Expression	[17]
Proto-oncogene tyrosine-protein kinase Src (SRC)	OTETYX40	SRC_HUMAN	Decreases Expression	[23]
Tissue factor (F3)	OT3MSU3B	TF_HUMAN	Decreases Expression	[24]
Tyrosine-protein kinase receptor UFO (AXL)	OTKA2SUX	UFO_HUMAN	Decreases Expression	[25]
Transcription factor Sp3 (SP3)	OTYDQZ1T	SP3_HUMAN	Decreases Expression	[17]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[26]
Epidermal growth factor receptor kinase substrate 8 (EPS8)	OTZ6ES6V	EPS8_HUMAN	Decreases Expression	[23]
TNFAIP3-interacting protein 1 (TNIP1)	OTRAOTEW	TNIP1_HUMAN	Decreases Expression	[27]
Sphingomyelin phosphodiesterase 3 (SMPD3)	OTHQBETH	NSMA2_HUMAN	Decreases Expression	[28]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Breast adenocarcinoma	DCMXU67	MDA-MB-468	Investigative	[29]
Carcinoma	DC8EG5B	RXF 393	Investigative	[29]
Carcinoma	DC4MX92	MCF7	Investigative	[29]
Colon adenocarcinoma	DCFG64T	COLO 205	Investigative	[29]
Colon carcinoma	DC1ZUME	KM12	Investigative	[29]
Invasive ductal carcinoma	DCXL1JX	HS 578T	Investigative	[29]
Invasive ductal carcinoma	DCSVKD2	BT-549	Investigative	[29]
Invasive ductal carcinoma	DC075PN	T-47D	Investigative	[29]
Adenocarcinoma	DC2KTUU	OVCAR3	Investigative	[1]
Adenocarcinoma	DC1RR2M	HCC-2998	Investigative	[1]
Adenocarcinoma	DC2MQOI	SW-620	Investigative	[1]
Adult acute myeloid leukemia	DC0N9PP	HL-60(TB)	Investigative	[1]
Adult T acute lymphoblastic leukemia	DCYRQMC	MOLT-4	Investigative	[1]
Amelanotic melanoma	DC4A7V8	M14	Investigative	[1]
Amelanotic melanoma	DCMGISY	MDA-MB-435	Investigative	[1]
Anaplastic large cell lymphoma	DC4V16Y	SR	Investigative	[1]
Astrocytoma	DCRV7HJ	U251	Investigative	[1]
Astrocytoma	DC16JX9	SNB-19	Investigative	[1]
Childhood T acute lymphoblastic leukemia	DCTSJJX	CCRF-CEM	Investigative	[1]
Chronic myelogenous leukemia	DCU3OPO	K-562	Investigative	[1]
Clear cell renal cell carcinoma	DCXJP64	786-0	Investigative	[1]
Clear cell renal cell carcinoma	DCX5T9P	A498	Investigative	[1]
Clear cell renal cell carcinoma	DC1CX8P	TK-10	Investigative	[1]
Clear cell renal cell carcinoma	DCESLPW	CAKI-1	Investigative	[1]
Cutaneous melanoma	DC9749A	SK-MEL-28	Investigative	[1]
Cutaneous melanoma	DCM0HO4	SK-MEL-5	Investigative	[1]
Glioblastoma	DC5ITWK	SNB-75	Investigative	[1]
Glioma	DCMCFDA	SF-268	Investigative	[1]
Glioma	DC7VTDP	SF-295	Investigative	[1]
Glioma	DCL880I	SF-539	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCWYWBU	OVCAR-4	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCLGCPM	OVCAR-8	Investigative	[1]
High grade ovarian serous adenocarcinoma	DC3CCR0	OVCAR-5	Investigative	[1]
Large cell lung carcinoma	DC8T1LI	NCI-H460	Investigative	[1]
Malignant melanoma	DCMN2WW	UACC62	Investigative	[1]
Melanoma	DCPUVQO	SK-MEL-2	Investigative	[1]
Melanoma	DCSJF9W	UACC-257	Investigative	[1]
Minimally invasive lung adenocarcinoma	DCF0Q6H	NCI-H322M	Investigative	[1]
Ovarian serous cystadenocarcinoma	DCHXIWX	SK-OV-3	Investigative	[1]
Papillary renal cell carcinoma	DCIQWLL	ACHN	Investigative	[1]
Plasma cell myeloma	DCFBSJ0	RPMI-8226	Investigative	[1]
Pleural epithelioid mesothelioma	DCAQR6T	NCI-H226	Investigative	[1]
Renal cell carcinoma	DCFH1B7	UO-31	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] 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).
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [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: 8394).
• [5] The Pluripotency Factor Musashi-2 Is a Novel Target for Lung Cancer Therapy.Ann Am Thorac Soc. 2018 Apr;15(Supplement_2):S124.
• [6] 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.
• [7] Tyrosine kinase inhibitors and multidrug resistance proteins: interactions and biological consequences. Cancer Chemother Pharmacol. 2010 Jan;65(2):335-46.
• [8] Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013 Mar 15;19(6):1458-66.
• [9] FDA label of Vandetanib. The 2020 official website of the U.S. Food and Drug Administration.
• [10] The RET oncogene is a critical component of transcriptional programs associated with retinoic acid-induced differentiation in neuroblastoma. Mol Cancer Ther. 2007 Apr;6(4):1300-9.
• [11] 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.
• [12] Anticancer effects of ZD6474, a VEGF receptor tyrosine kinase inhibitor, in gefitinib ("Iressa")-sensitive and resistant xenograft models. Cancer Sci. 2004 Dec;95(12):984-9. doi: 10.1111/j.1349-7006.2004.tb03187.x.
• [13] Cytotoxicity of 34 FDA approved small-molecule kinase inhibitors in primary rat and human hepatocytes. Toxicol Lett. 2018 Jul;291:138-148. doi: 10.1016/j.toxlet.2018.04.010. Epub 2018 Apr 12.
• [14] 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.
• [15] Downregulation of hERG channel expression by tyrosine kinase inhibitors nilotinib and vandetanib predominantly contributes to arrhythmogenesis. Toxicol Lett. 2022 Jul 15;365:11-23. doi: 10.1016/j.toxlet.2022.06.001. Epub 2022 Jun 6.
• [16] 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.
• [17] The activity of a novel mithramycin analog is related to its binding to DNA, cellular accumulation, and inhibition of Sp1-driven gene transcription. Chem Biol Interact. 2014 Aug 5;219:123-32. doi: 10.1016/j.cbi.2014.05.019. Epub 2014 Jun 4.
• [18] Role of magnesium ion in mithramycin-DNA interaction: binding of mithramycin-Mg2+ complexes with DNA. Biochemistry. 1995 Jan 31;34(4):1376-85.
• [19] SP1 and SP3 mediate progesterone-dependent induction of the 17beta hydroxysteroid dehydrogenase type 2 gene in human endometrium. Biol Reprod. 2006 Oct;75(4):605-14.
• [20] Metformin suppresses CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating aryl hydrocarbon receptor expression. Toxicol Appl Pharmacol. 2014 Oct 1;280(1):138-48.
• [21] Molecular mechanisms of transactivation and doxorubicin-mediated repression of survivin gene in cancer cells. J Biol Chem. 2007 Jan 26;282(4):2615-25. doi: 10.1074/jbc.M606203200. Epub 2006 Nov 22.
• [22] Sp1 and Sp3 transcription factors regulate the basal expression of human microsomal epoxide hydrolase (EPHX1) through interaction with the E1b far upstream promoter. Gene. 2014 Feb 15;536(1):135-44. doi: 10.1016/j.gene.2013.11.053. Epub 2013 Dec 4.
• [23] Mithramycin inhibits human epithelial carcinoma cell proliferation and migration involving downregulation of Eps8 expression. Chem Biol Interact. 2010 Jan 5;183(1):181-6. doi: 10.1016/j.cbi.2009.09.018.
• [24] Asbestos induces tissue factor in Beas-2B human lung bronchial epithelial cells in vitro. Lung. 2004;182(4):251-64. doi: 10.1007/s00408-004-2507-2.
• [25] The human receptor tyrosine kinase Axl gene--promoter characterization and regulation of constitutive expression by Sp1, Sp3 and CpG methylation. Biosci Rep. 2008 Jun;28(3):161-76. doi: 10.1042/BSR20080046.
• [26] CREB/Sp1-mediated MCL1 expression and NFB-mediated ABCB1 expression modulate the cytotoxicity of daunorubicin in chronic myeloid leukemia cells. Toxicol Appl Pharmacol. 2022 Jan 15;435:115847. doi: 10.1016/j.taap.2021.115847. Epub 2021 Dec 25.
• [27] Sp sites contribute to basal and inducible expression of the human TNIP1 (TNF-inducible protein 3-interacting protein 1) promoter. Biochem J. 2013 Jun 15;452(3):519-29. doi: 10.1042/BJ20121666.
• [28] Transcriptional regulation of neutral sphingomyelinase 2 gene expression of a human breast cancer cell line, MCF-7, induced by the anti-cancer drug, daunorubicin. Biochim Biophys Acta. 2009 Nov-Dec;1789(11-12):681-90. doi: 10.1016/j.bbagrm.2009.08.006. Epub 2009 Aug 19.
• [29] 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.