Details of the Drug Combination

General Information of Drug Combination (ID: DC7OVNJ)

• Drug Combination Name: Vandetanib + Mechlorethamine
• Indication: Malignant melanoma; Status: Investigative [1]
• Component Drugs:
  Vandetanib (DMRICNP): Small molecular drug
  Mechlorethamine (DM0CVXA): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: LOX IMVI
  Zero Interaction Potency (ZIP) Score: 3.44
  Bliss Independence Score: 4.61
  Loewe Additivity Score: 7.02
  LHighest Single Agent (HSA) Score: 7.79

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 Mechlorethamine

Disease Entry	ICD 11	Status	REF
Chronic myelogenous leukaemia	2A20.0	Approved	[3]
Lung cancer	2C25.0	Approved	[3]
Mycosis fungoides	2B01	Approved	[3]
Primary cutaneous T-cell lymphoma	N.A.	Approved	[3]
Small lymphocytic lymphoma	2A82.0	Approved	[3]
T-cell lymphoma	2A90	Approved	[4]
Hodgkin lymphoma	2B30	Phase 3	[5]
Classic Hodgkin lymphoma	N.A.	Investigative	[3]

Mechlorethamine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human Deoxyribonucleic acid (hDNA)	TTUTN1I	NOUNIPROTAC	Intercalator	[19]

Mechlorethamine Interacts with 19 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Receptor tyrosine-protein kinase erbB-2 (ERBB2)	OTOAUNCK	ERBB2_HUMAN	Decreases Expression	[20]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Decreases Activity	[21]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Increases Expression	[22]
Cyclin-dependent kinase 1 (CDK1)	OTW1SC2N	CDK1_HUMAN	Decreases Activity	[23]
Glutathione S-transferase A2 (GSTA2)	OTW7UB1H	GSTA2_HUMAN	Increases Expression	[24]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[22]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[25]
G2/mitotic-specific cyclin-B1 (CCNB1)	OT19S7E5	CCNB1_HUMAN	Decreases Activity	[23]
Transcription factor JunB (JUNB)	OTG2JXV5	JUNB_HUMAN	Increases Expression	[22]
Transcription factor JunD (JUND)	OTNKACJD	JUND_HUMAN	Increases Expression	[22]
Cyclin-A2 (CCNA2)	OTPHHYZJ	CCNA2_HUMAN	Increases Stability	[23]
Cyclin-dependent kinase 2 (CDK2)	OTB5DYYZ	CDK2_HUMAN	Increases Activity	[23]
Protein S100-P (S100P)	OTJCXNJG	S100P_HUMAN	Increases Expression	[26]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[27]
Caspase-2 (CASP2)	OTUDYSPP	CASP2_HUMAN	Increases Activity	[25]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[25]
Laminin subunit gamma-2 (LAMC2)	OTJMTM72	LAMC2_HUMAN	Decreases Expression	[28]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Increases Expression	[29]
Transient receptor potential cation channel subfamily A member 1 (TRPA1)	OTRDIR5M	TRPA1_HUMAN	Increases Response To Substance	[30]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adult acute myeloid leukemia	DCT445E	HL-60(TB)	Investigative	[1]
Amelanotic melanoma	DCO73AM	MDA-MB-435	Investigative	[1]
Plasma cell myeloma	DCEX87T	RPMI-8226	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] Mechlorethamine FDA Label
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] 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: 7218).
• [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] Thioredoxin Cross-Linking by Nitrogen Mustard in Lung Epithelial Cells: Formation of Multimeric Thioredoxin/Thioredoxin Reductase Complexes and Inhibition of Disulfide Reduction. Chem Res Toxicol. 2015 Nov 16;28(11):2091-103. doi: 10.1021/acs.chemrestox.5b00194. Epub 2015 Oct 19.
• [18] Cross-linking of thioredoxin reductase by the sulfur mustard analogue mechlorethamine (methylbis(2-chloroethyl)amine) in human lung epithelial cells and rat lung: selective inhibition of disulfide reduction but not redox cycling. Chem Res Toxicol. 2014 Jan 21;27(1):61-75. doi: 10.1021/tx400329a. Epub 2013 Dec 9.
• [19] Proteomic analysis of DNA-protein cross-linking by antitumor nitrogen mustards. Chem Res Toxicol. 2009 Jun;22(6):1151-62.
• [20] Down-regulation of HER-2 expression in human breast cancer cell HBC-4 and ZR75-1 by nitrogen-mustard-N-oxide. Kobe J Med Sci. 2007;53(4):135-42.
• [21] Nitrogen Mustard Alkylates and Cross-Links p53 in Human Keratinocytes. Chem Res Toxicol. 2022 Apr 18;35(4):636-650. doi: 10.1021/acs.chemrestox.1c00420. Epub 2022 Mar 21.
• [22] Nitrogen mustard prevents transport of Fra-1 into the nucleus to promote c-Fos- and FosB-dependent IL-8 induction in injured mouse epidermis. Toxicol Lett. 2020 Feb 1;319:256-263. doi: 10.1016/j.toxlet.2019.10.006. Epub 2019 Oct 19.
• [23] G2 delay induced by nitrogen mustard in human cells affects cyclin A/cdk2 and cyclin B1/cdc2-kinase complexes differently. J Biol Chem. 1993 Apr 15;268(11):8298-308.
• [24] Overexpression of GSTA2 protects against cell cycle arrest and apoptosis induced by the DNA inter-strand crosslinking nitrogen mustard, mechlorethamine. J Cell Biochem. 2005 May 15;95(2):339-51. doi: 10.1002/jcb.20440.
• [25] Inhibition of caspase-dependent mitochondrial permeability transition protects airway epithelial cells against mustard-induced apoptosis. Apoptosis. 2006 Sep;11(9):1545-59. doi: 10.1007/s10495-006-8764-1.
• [26] S100P is selectively upregulated in tumor cell lines challenged with DNA cross-linking agents. Leuk Res. 2005 Oct;29(10):1181-90. doi: 10.1016/j.leukres.2005.03.012.
• [27] Ebselen reduces the toxicity of mechlorethamine in A-431 cells via inhibition of apoptosis. J Biochem Mol Toxicol. 2013 Jun;27(6):313-22. doi: 10.1002/jbt.21490. Epub 2013 May 6.
• [28] Histopathologic and immunohistochemical features in human skin after exposure to nitrogen and sulfur mustard. Am J Dermatopathol. 1998 Feb;20(1):22-8. doi: 10.1097/00000372-199802000-00005.
• [29] Increased expression of VDAC1 sensitizes carcinoma cells to apoptosis induced by DNA cross-linking agents. Biochem Pharmacol. 2012 May 1;83(9):1172-82. doi: 10.1016/j.bcp.2012.01.017. Epub 2012 Jan 21.
• [30] Activation of the human TRPA1 channel by different alkylating sulfur and nitrogen mustards and structurally related chemotherapeutic drugs. Toxicol Lett. 2023 Mar 1;376:51-59. doi: 10.1016/j.toxlet.2023.01.007. Epub 2023 Jan 21.