Details of the Drug Combination

General Information of Drug Combination (ID: DC4XX3L)

• Drug Combination Name: Vismodegib + Valrubicin
• Indication: Plasma cell myeloma; Status: Investigative [1]
• Component Drugs:
  Vismodegib (DM5IXKQ): Small molecular drug
  Valrubicin (DMOYJFK): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: RPMI-8226
  Zero Interaction Potency (ZIP) Score: 7.46
  Bliss Independence Score: 12.05
  Loewe Additivity Score: 4.69
  LHighest Single Agent (HSA) Score: 4.96

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 Valrubicin

Disease Entry	ICD 11	Status	REF
Bladder cancer	2C94	Approved	[4]
In situ carcinoma	N.A.	Approved	[5]
Urinary bladder cancer	N.A.	Approved	[5]
Psoriasis vulgaris	EA90	Phase 2	[6]

Valrubicin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
DNA topoisomerase II (TOP2)	TT0IHXV	TOP2A_HUMAN; TOP2B_HUMAN	Inhibitor	[11]

Valrubicin Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[12]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Invasive ductal carcinoma	DCZYQB1	BT-549	Investigative	[13]
Invasive ductal carcinoma	DCIK1TP	HS 578T	Investigative	[13]
Adenocarcinoma	DC3VA59	DU-145	Investigative	[1]
Adult acute myeloid leukemia	DCBYU0Y	HL-60(TB)	Investigative	[1]
Amelanotic melanoma	DCA8YMV	M14	Investigative	[1]
Clear cell renal cell carcinoma	DCPW869	786-0	Investigative	[1]
Cutaneous melanoma	DCX6DXV	SK-MEL-28	Investigative	[1]
Cutaneous melanoma	DCAWDSX	SK-MEL-5	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCR0RRW	OVCAR-5	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCNUUMQ	OVCAR-8	Investigative	[1]
Large cell lung carcinoma	DCXLLZG	NCI-H460	Investigative	[1]
Lung adenocarcinoma	DC098WJ	HOP-62	Investigative	[1]
Malignant melanoma	DCP8U6R	LOX IMVI	Investigative	[1]
Melanoma	DCHNJH3	UACC-257	Investigative	[1]
Melanoma	DCQH126	SK-MEL-2	Investigative	[1]
Melanoma	DCROUAQ	MALME-3M	Investigative	[1]
Renal cell carcinoma	DCT3N2H	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: 6975).
• [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] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [5] Valrubicin FDA Label
• [6] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [7] Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
• [8] The dawn of hedgehog inhibitors: Vismodegib. J Pharmacol Pharmacother. 2013 Jan;4(1):4-7.
• [9] Hedgehog signaling antagonist GDC-0449 (Vismodegib) inhibits pancreatic cancer stem cell characteristics: molecular mechanisms. PLoS One. 2011;6(11):e27306. doi: 10.1371/journal.pone.0027306. Epub 2011 Nov 8.
• [10] Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition. Nat Med. 2014 Jul;20(7):732-40. doi: 10.1038/nm.3613. Epub 2014 Jun 29.
• [11] Metabolic activation of N-acylanthracyclines precedes their interaction with DNA topoisomerase II. NCI Monogr. 1987;(4):111-5.
• [12] A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol Sci. 2013 Nov;136(1):216-41.
• [13] 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.