Details of the Drug Combination

General Information of Drug Combination (ID: DCV0G8A)

• Drug Combination Name: Crizotinib + Mechlorethamine
• Indication: Adult T acute lymphoblastic leukemia; Status: Investigative [1]
• Component Drugs:
  Crizotinib (DM4F29C): Small molecular drug
  Mechlorethamine (DM0CVXA): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: MOLT-4
  Zero Interaction Potency (ZIP) Score: 4.7
  Bliss Independence Score: 8.87
  Loewe Additivity Score: 5.68
  LHighest Single Agent (HSA) Score: 7.92

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Crizotinib

Disease Entry	ICD 11	Status	REF
Non-small-cell lung cancer	2C25.Y	Approved	[2]

Crizotinib Interacts with 4 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Proto-oncogene c-Met (MET)	TTNDSF4	MET_HUMAN	Modulator	[4]
ALK tyrosine kinase receptor (ALK)	TTPMQSO	ALK_HUMAN	Modulator	[4]
Proto-oncogene c-Ros (ROS1)	TTSZ6Y3	ROS1_HUMAN	Modulator	[4]
HGF/Met signaling pathway (HGF/Met pathway)	TTKA5LP	NOUNIPROTAC	Inhibitor	[9]

Crizotinib Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[10]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[11]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[11]

Crizotinib Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[12]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[12]

Crizotinib Interacts with 24 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Activity	[13]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Response To Substance	[7]
CD44 antigen (CD44)	OT9TTJ41	CD44_HUMAN	Decreases Expression	[6]
Epithelial cell adhesion molecule (EPCAM)	OTHBZK5X	EPCAM_HUMAN	Decreases Expression	[6]
Insulin-induced gene 1 protein (INSIG1)	OTZF5X1D	INSI1_HUMAN	Increases Expression	[14]
Hydroxymethylglutaryl-CoA synthase, cytoplasmic (HMGCS1)	OTCO26FV	HMCS1_HUMAN	Increases Expression	[14]
Sterol regulatory element-binding protein 2 (SREBF2)	OTBXUNPL	SRBP2_HUMAN	Increases Expression	[14]
Acetyl-CoA carboxylase 1 (ACACA)	OT5CQPZY	ACACA_HUMAN	Increases Phosphorylation	[14]
Voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C)	OT6KFNMS	CAC1C_HUMAN	Decreases Activity	[14]
Sodium channel protein type 5 subunit alpha (SCN5A)	OTGYZWR6	SCN5A_HUMAN	Decreases Activity	[14]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[7]
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[7]
Follitropin subunit beta (FSHB)	OTGLS283	FSHB_HUMAN	Decreases Secretion	[15]
Lutropin subunit beta (LHB)	OT5GBOVJ	LSHB_HUMAN	Decreases Secretion	[15]
Tyrosine-protein kinase Lck (LCK)	OT883FG9	LCK_HUMAN	Decreases Activity	[16]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[17]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Phosphorylation	[17]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[18]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[18]
Ras GTPase-activating-like protein IQGAP1 (IQGAP1)	OTZRWTGA	IQGA1_HUMAN	Decreases Phosphorylation	[19]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Decreases Phosphorylation	[20]
Baculoviral IAP repeat-containing protein 2 (BIRC2)	OTFXFREP	BIRC2_HUMAN	Decreases Expression	[7]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Decreases Activity	[13]
Mast/stem cell growth factor receptor Kit (KIT)	OTHUY3VZ	KIT_HUMAN	Decreases Response To Substance	[21]

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	[24]

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	[25]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Increases Expression	[26]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[26]
Transcription factor JunB (JUNB)	OTG2JXV5	JUNB_HUMAN	Increases Expression	[26]
Transcription factor JunD (JUND)	OTNKACJD	JUND_HUMAN	Increases Expression	[26]
Protein S100-P (S100P)	OTJCXNJG	S100P_HUMAN	Increases Expression	[27]
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
Plasma cell myeloma	DCDI92C	RPMI-8226	Investigative	[1]
Renal cell carcinoma	DCFZYZA	SN12C	Investigative	[1]
Invasive ductal carcinoma	DCGUPUO	T-47D	Investigative	[31]

References

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• [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).
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• [20] Crizotinib-resistant mutants of EML4-ALK identified through an accelerated mutagenesis screen. Chem Biol Drug Des. 2011 Dec;78(6):999-1005. doi: 10.1111/j.1747-0285.2011.01239.x. Epub 2011 Oct 31.
• [21] Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med. 2012 Feb 8;4(120):120ra17. doi: 10.1126/scitranslmed.3003316. Epub 2012 Jan 25.
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• [23] 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.
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