Details of the Drug Combination

General Information of Drug Combination (ID: DCS2BV2)

• Drug Combination Name: Vismodegib + Mechlorethamine
• Indication: Adult acute myeloid leukemia; Status: Investigative [1]
• Component Drugs:
  Vismodegib (DM5IXKQ): Small molecular drug
  Mechlorethamine (DM0CVXA): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: HL-60(TB)
  Zero Interaction Potency (ZIP) Score: 13.28
  Bliss Independence Score: 13.52
  Loewe Additivity Score: 5.97
  LHighest Single Agent (HSA) Score: 10.41

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Vismodegib

Disease Entry	ICD 11	Status	REF
Basal cell carcinoma	2C32	Approved	[2]
Primitive neuroectodermal tumour medulloblastoma	2A00.11	Phase 2	[3]

Vismodegib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Smoothened homolog (SMO)	TT8J1S3	SMO_HUMAN	Modulator	[7]

Vismodegib Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[8]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[8]

Vismodegib Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Tumor necrosis factor receptor superfamily member 10A (TNFRSF10A)	OTBPCU2O	TR10A_HUMAN	Increases Expression	[9]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[9]
Zinc finger protein GLI1 (GLI1)	OT1BTAJO	GLI1_HUMAN	Decreases Expression	[9]
Zinc finger protein GLI2 (GLI2)	OTIRV97L	GLI2_HUMAN	Decreases Expression	[9]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[9]
Platelet-derived growth factor receptor alpha (PDGFRA)	OTDJXUCN	PGFRA_HUMAN	Decreases Expression	[9]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[9]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[9]
Protein patched homolog 1 (PTCH1)	OTMG07H5	PTC1_HUMAN	Decreases Expression	[9]
Protein smoothened (SMO)	OTXXE208	SMO_HUMAN	Decreases Expression	[9]
Protein patched homolog 2 (PTCH2)	OTOQ0K9V	PTC2_HUMAN	Decreases Expression	[9]
Suppressor of fused homolog (SUFU)	OT0IRYG1	SUFU_HUMAN	Decreases Response To Substance	[10]
N-myc proto-oncogene protein (MYCN)	OTWD33K1	MYCN_HUMAN	Decreases Response To Substance	[10]

Indication(s) of Mechlorethamine

Disease Entry	ICD 11	Status	REF
Chronic myelogenous leukaemia	2A20.0	Approved	[4]
Lung cancer	2C25.0	Approved	[4]
Mycosis fungoides	2B01	Approved	[4]
Primary cutaneous T-cell lymphoma	N.A.	Approved	[4]
Small lymphocytic lymphoma	2A82.0	Approved	[4]
T-cell lymphoma	2A90	Approved	[5]
Hodgkin lymphoma	2B30	Phase 3	[6]
Classic Hodgkin lymphoma	N.A.	Investigative	[4]

Mechlorethamine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human Deoxyribonucleic acid (hDNA)	TTUTN1I	NOUNIPROTAC	Intercalator	[13]

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	[14]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Decreases Activity	[15]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Increases Expression	[16]
Cyclin-dependent kinase 1 (CDK1)	OTW1SC2N	CDK1_HUMAN	Decreases Activity	[17]
Glutathione S-transferase A2 (GSTA2)	OTW7UB1H	GSTA2_HUMAN	Increases Expression	[18]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[16]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[19]
G2/mitotic-specific cyclin-B1 (CCNB1)	OT19S7E5	CCNB1_HUMAN	Decreases Activity	[17]
Transcription factor JunB (JUNB)	OTG2JXV5	JUNB_HUMAN	Increases Expression	[16]
Transcription factor JunD (JUND)	OTNKACJD	JUND_HUMAN	Increases Expression	[16]
Cyclin-A2 (CCNA2)	OTPHHYZJ	CCNA2_HUMAN	Increases Stability	[17]
Cyclin-dependent kinase 2 (CDK2)	OTB5DYYZ	CDK2_HUMAN	Increases Activity	[17]
Protein S100-P (S100P)	OTJCXNJG	S100P_HUMAN	Increases Expression	[20]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[21]
Caspase-2 (CASP2)	OTUDYSPP	CASP2_HUMAN	Increases Activity	[19]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[19]
Laminin subunit gamma-2 (LAMC2)	OTJMTM72	LAMC2_HUMAN	Decreases Expression	[22]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Increases Expression	[23]
Transient receptor potential cation channel subfamily A member 1 (TRPA1)	OTRDIR5M	TRPA1_HUMAN	Increases Response To Substance	[24]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adenocarcinoma	DCZB6M0	SW-620	Investigative	[1]
Astrocytoma	DCP6JLN	SNB-19	Investigative	[1]
Renal cell carcinoma	DCG69HU	SN12C	Investigative	[1]

References

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• [3] A phase II, multicenter, open-label, 3-cohort trial evaluating the efficacy and safety of vismodegib in operable basal cell carcinoma. J Am Acad Dermatol. 2015 Jul;73(1):99-105.e1.
• [4] Mechlorethamine FDA Label
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
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• [17] 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.
• [18] 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.
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• [21] 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.
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