Details of the Drug Combination

General Information of Drug Combination (ID: DC1BDZS)

• Drug Combination Name: Vismodegib + Plicamycin
• Indication: Adenocarcinoma; Status: Investigative [1]
• Component Drugs:
  Vismodegib (DM5IXKQ): Small molecular drug
  Plicamycin (DM7C8YV): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: HCT-15
  Zero Interaction Potency (ZIP) Score: 3.89
  Bliss Independence Score: 3.49
  Loewe Additivity Score: 2.7
  LHighest Single Agent (HSA) Score: 2.63

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 8 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 GLI2 (GLI2)	OTIRV97L	GLI2_HUMAN	Decreases Expression	[9]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[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]

Indication(s) of Plicamycin

Disease Entry	ICD 11	Status	REF
Hypercalcaemia	5B91.0	Approved	[4]
Testicular cancer	2C80	Approved	[4]
Solid tumour/cancer	2A00-2F9Z	Withdrawn from market	[5]
Lung cancer	2C25.0	Investigative	[6]
Ovarian cancer	2C73	Investigative	[6]

Plicamycin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
RNA synthesis (hRNA synth)	TTX2AYW	NOUNIPROTAC	Modulator	[12]

Plicamycin Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
17-beta-hydroxysteroid dehydrogenase type 2 (HSD17B2)	OT3K7HY5	DHB2_HUMAN	Decreases Expression	[13]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[14]
Proto-oncogene tyrosine-protein kinase Src (SRC)	OTETYX40	SRC_HUMAN	Decreases Expression	[15]
Tyrosine-protein kinase receptor UFO (AXL)	OTKA2SUX	UFO_HUMAN	Decreases Expression	[16]
Transcription factor Sp3 (SP3)	OTYDQZ1T	SP3_HUMAN	Decreases Expression	[11]
Epidermal growth factor receptor kinase substrate 8 (EPS8)	OTZ6ES6V	EPS8_HUMAN	Decreases Expression	[15]
TNFAIP3-interacting protein 1 (TNIP1)	OTRAOTEW	TNIP1_HUMAN	Decreases Expression	[17]
Sphingomyelin phosphodiesterase 3 (SMPD3)	OTHQBETH	NSMA2_HUMAN	Decreases Expression	[18]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Breast adenocarcinoma	DCLEA4E	MDA-MB-468	Investigative	[19]
Carcinoma	DCBKWNH	RXF 393	Investigative	[19]
Carcinoma	DCGGB2G	MCF7	Investigative	[19]
Colon adenocarcinoma	DCB1RJN	COLO 205	Investigative	[19]
Colon carcinoma	DCIHIS4	KM12	Investigative	[19]
Invasive ductal carcinoma	DC7MKIN	HS 578T	Investigative	[19]
Invasive ductal carcinoma	DC1JVD5	BT-549	Investigative	[19]
Invasive ductal carcinoma	DCMEQRO	T-47D	Investigative	[19]
Adenocarcinoma	DCTXME4	DU-145	Investigative	[1]
Adenocarcinoma	DCG2MMK	OVCAR3	Investigative	[1]
Adenocarcinoma	DCM5SO5	NCIH23	Investigative	[1]
Adenocarcinoma	DCVBNR2	A549	Investigative	[1]
Adenocarcinoma	DCX2KEU	SW-620	Investigative	[1]
Adenocarcinoma	DCKN4FX	HT29	Investigative	[1]
Adenocarcinoma	DCCUBBT	HCT116	Investigative	[1]
Adenocarcinoma	DCQV22I	HCC-2998	Investigative	[1]
Adult acute myeloid leukemia	DCPXMVW	HL-60(TB)	Investigative	[1]
Adult T acute lymphoblastic leukemia	DCC6DIU	MOLT-4	Investigative	[1]
Amelanotic melanoma	DCCZ9ZH	M14	Investigative	[1]
Amelanotic melanoma	DCGDOKI	MDA-MB-435	Investigative	[1]
Anaplastic large cell lymphoma	DC7NMBP	SR	Investigative	[1]
Astrocytoma	DCRJWU1	U251	Investigative	[1]
Astrocytoma	DCW91Z3	SNB-19	Investigative	[1]
Childhood T acute lymphoblastic leukemia	DCS9T4Y	CCRF-CEM	Investigative	[1]
Chronic myelogenous leukemia	DCZQRX8	K-562	Investigative	[1]
Clear cell renal cell carcinoma	DCKN4HV	TK-10	Investigative	[1]
Clear cell renal cell carcinoma	DCCHRLV	786-0	Investigative	[1]
Clear cell renal cell carcinoma	DCHJ0BT	A498	Investigative	[1]
Clear cell renal cell carcinoma	DC73YCW	CAKI-1	Investigative	[1]
Cutaneous melanoma	DCBCLMM	SK-MEL-5	Investigative	[1]
Cutaneous melanoma	DC9TDZB	SK-MEL-28	Investigative	[1]
Glioblastoma	DCJWXRD	SNB-75	Investigative	[1]
Glioma	DCA2JMR	SF-539	Investigative	[1]
Glioma	DCO0DKH	SF-268	Investigative	[1]
Glioma	DCUO9ZK	SF-295	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCQMY29	OVCAR-5	Investigative	[1]
High grade ovarian serous adenocarcinoma	DC4B6II	OVCAR-8	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCG83A6	OVCAR-4	Investigative	[1]
Large cell lung carcinoma	DCGOKUU	NCI-H460	Investigative	[1]
Lung adenocarcinoma	DC4KTV5	MDA-MB-231	Investigative	[1]
Lung adenocarcinoma	DCY9RJ5	EKVX	Investigative	[1]
Lung adenocarcinoma	DCB4OVA	HOP-62	Investigative	[1]
Lung adenocarcinoma	DCZQ6NC	NCI-H522	Investigative	[1]
Malignant melanoma	DCSNYNM	UACC62	Investigative	[1]
Malignant melanoma	DC5RVLC	LOX IMVI	Investigative	[1]
Melanoma	DCQZCEW	SK-MEL-2	Investigative	[1]
Melanoma	DCFCDEV	UACC-257	Investigative	[1]
Melanoma	DC7AS3H	MALME-3M	Investigative	[1]
Minimally invasive lung adenocarcinoma	DC63WZ7	NCI-H322M	Investigative	[1]
Mixed endometrioid and clear cell carcinoma	DC3NCKM	IGROV1	Investigative	[1]
Non-small cell lung carcinoma	DCWU77T	HOP-92	Investigative	[1]
Ovarian serous cystadenocarcinoma	DCZ20C5	SK-OV-3	Investigative	[1]
Papillary renal cell carcinoma	DCKX3NP	ACHN	Investigative	[1]
Plasma cell myeloma	DC0B4ID	RPMI-8226	Investigative	[1]
Pleural epithelioid mesothelioma	DCVJQT0	NCI-H226	Investigative	[1]
Prostate carcinoma	DCV43TU	PC-3	Investigative	[1]
Renal cell carcinoma	DCLRXZY	UO-31	Investigative	[1]
Renal cell carcinoma	DCL41I9	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] 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: 8394).
• [6] The Pluripotency Factor Musashi-2 Is a Novel Target for Lung Cancer Therapy.Ann Am Thorac Soc. 2018 Apr;15(Supplement_2):S124.
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• [11] The activity of a novel mithramycin analog is related to its binding to DNA, cellular accumulation, and inhibition of Sp1-driven gene transcription. Chem Biol Interact. 2014 Aug 5;219:123-32. doi: 10.1016/j.cbi.2014.05.019. Epub 2014 Jun 4.
• [12] Role of magnesium ion in mithramycin-DNA interaction: binding of mithramycin-Mg2+ complexes with DNA. Biochemistry. 1995 Jan 31;34(4):1376-85.
• [13] SP1 and SP3 mediate progesterone-dependent induction of the 17beta hydroxysteroid dehydrogenase type 2 gene in human endometrium. Biol Reprod. 2006 Oct;75(4):605-14.
• [14] Molecular mechanisms of transactivation and doxorubicin-mediated repression of survivin gene in cancer cells. J Biol Chem. 2007 Jan 26;282(4):2615-25. doi: 10.1074/jbc.M606203200. Epub 2006 Nov 22.
• [15] Mithramycin inhibits human epithelial carcinoma cell proliferation and migration involving downregulation of Eps8 expression. Chem Biol Interact. 2010 Jan 5;183(1):181-6. doi: 10.1016/j.cbi.2009.09.018.
• [16] The human receptor tyrosine kinase Axl gene--promoter characterization and regulation of constitutive expression by Sp1, Sp3 and CpG methylation. Biosci Rep. 2008 Jun;28(3):161-76. doi: 10.1042/BSR20080046.
• [17] Sp sites contribute to basal and inducible expression of the human TNIP1 (TNF-inducible protein 3-interacting protein 1) promoter. Biochem J. 2013 Jun 15;452(3):519-29. doi: 10.1042/BJ20121666.
• [18] Transcriptional regulation of neutral sphingomyelinase 2 gene expression of a human breast cancer cell line, MCF-7, induced by the anti-cancer drug, daunorubicin. Biochim Biophys Acta. 2009 Nov-Dec;1789(11-12):681-90. doi: 10.1016/j.bbagrm.2009.08.006. Epub 2009 Aug 19.
• [19] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1126165