Details of the Drug Combination

General Information of Drug Combination (ID: DCFD93E)

• Drug Combination Name: Mechlorethamine + Vemurafenib
• Indication: Carcinoma; Status: Investigative [1]
• Component Drugs:
  Mechlorethamine (DM0CVXA): Small molecular drug
  Vemurafenib (DM62UG5): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: MCF7
  Zero Interaction Potency (ZIP) Score: 1.09
  Bliss Independence Score: 2.6
  Loewe Additivity Score: 0.8
  LHighest Single Agent (HSA) Score: 1.04

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Mechlorethamine

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

Mechlorethamine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human Deoxyribonucleic acid (hDNA)	TTUTN1I	NOUNIPROTAC	Intercalator	[8]

Mechlorethamine Interacts with 9 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	[9]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Increases Expression	[10]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[10]
Transcription factor JunB (JUNB)	OTG2JXV5	JUNB_HUMAN	Increases Expression	[10]
Transcription factor JunD (JUND)	OTNKACJD	JUND_HUMAN	Increases Expression	[10]
Protein S100-P (S100P)	OTJCXNJG	S100P_HUMAN	Increases Expression	[11]
Laminin subunit gamma-2 (LAMC2)	OTJMTM72	LAMC2_HUMAN	Decreases Expression	[12]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Increases Expression	[13]
Transient receptor potential cation channel subfamily A member 1 (TRPA1)	OTRDIR5M	TRPA1_HUMAN	Increases Response To Substance	[14]

Indication(s) of Vemurafenib

Disease Entry	ICD 11	Status	REF
Melanoma	2C30	Approved	[5]

Vemurafenib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Serine/threonine-protein kinase B-raf (BRAF)	TTWCGQT	BRAF_HUMAN	Modulator	[3]

Vemurafenib Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[17]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[18]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[18]

Vemurafenib Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[19]

Vemurafenib Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Microphthalmia-associated transcription factor (MITF)	OT6XJCZH	MITF_HUMAN	Affects Expression	[15]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[20]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[21]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[16]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[16]
CD70 antigen (CD70)	OTHB2AL1	CD70_HUMAN	Decreases Expression	[22]
Melanocyte protein PMEL (PMEL)	OTCDDHHM	PMEL_HUMAN	Increases Expression	[15]
Melanoma antigen recognized by T-cells 1 (MLANA)	OT1N2S2K	MAR1_HUMAN	Increases Expression	[15]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Childhood T acute lymphoblastic leukemia	DCV5ZB4	CCRF-CEM	Investigative	[23]
Glioma	DCT3Z0O	SF-295	Investigative	[23]
Plasma cell myeloma	DC4H4OE	RPMI-8226	Investigative	[23]
Renal cell carcinoma	DCWF584	SN12C	Investigative	[23]
Invasive ductal carcinoma	DCCU4ZE	BT-549	Investigative	[1]
Adenocarcinoma	DCPMI2S	DU-145	Investigative	[24]
Adenocarcinoma	DCSNA4K	A549	Investigative	[24]
Adenocarcinoma	DCW3LT4	HCT-15	Investigative	[24]
Lung adenocarcinoma	DCWXGMJ	MDA-MB-231	Investigative	[24]
Lung adenocarcinoma	DCV4RGA	EKVX	Investigative	[24]
Minimally invasive lung adenocarcinoma	DC1DGAI	NCI-H322M	Investigative	[24]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1126165
• [2] Mechlorethamine FDA Label
• [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: 7218).
• [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: 5893).
• [6] 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.
• [7] 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.
• [8] Proteomic analysis of DNA-protein cross-linking by antitumor nitrogen mustards. Chem Res Toxicol. 2009 Jun;22(6):1151-62.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] PLX4032 Mediated Melanoma Associated Antigen Potentiation in Patient Derived Primary Melanoma Cells. J Cancer. 2015 Oct 29;6(12):1320-30. doi: 10.7150/jca.11126. eCollection 2015.
• [16] Actin remodeling confers BRAF inhibitor resistance to melanoma cells through YAP/TAZ activation. EMBO J. 2016 Mar 1;35(5):462-78. doi: 10.15252/embj.201592081. Epub 2015 Dec 14.
• [17] Differential effects of the oncogenic BRAF inhibitor PLX4032 (vemurafenib) and its progenitor PLX4720 on ABCB1 function. J Pharm Pharm Sci. 2014;17(1):154-68.
• [18] Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013 Mar 15;19(6):1458-66.
• [19] Vemurafenib for the treatment of melanoma. Expert Opin Pharmacother. 2012 Dec;13(17):2533-43.
• [20] Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells. Elife. 2015 Aug 18;4:e04640. doi: 10.7554/eLife.04640.
• [21] Overcoming melanoma resistance to vemurafenib by targeting CCL2-induced miR-34a, miR-100 and miR-125b. Oncotarget. 2016 Jan 26;7(4):4428-41. doi: 10.18632/oncotarget.6599.
• [22] Melanoma Expressed-CD70 Is Regulated by RhoA and MAPK Pathways without Affecting Vemurafenib Treatment Activity. PLoS One. 2016 Feb 1;11(2):e0148095. doi: 10.1371/journal.pone.0148095. eCollection 2016.
• [23] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [24] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125976