Details of the Drug Combination

General Information of Drug Combination (ID: DCG3579)

• Drug Combination Name: Vismodegib + Taxol
• Indication: Invasive ductal carcinoma; Status: Investigative [1]
• Component Drugs:
  Vismodegib (DM5IXKQ): Small molecular drug
  Taxol (DMUOT9V): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: BT-549
  Zero Interaction Potency (ZIP) Score: 9.27
  Bliss Independence Score: 9.99
  Loewe Additivity Score: 6.14
  LHighest Single Agent (HSA) Score: 9.73

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	[8]

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	[9]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[9]

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	[10]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[10]
Zinc finger protein GLI1 (GLI1)	OT1BTAJO	GLI1_HUMAN	Decreases Expression	[10]
Zinc finger protein GLI2 (GLI2)	OTIRV97L	GLI2_HUMAN	Decreases Expression	[10]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[10]
Platelet-derived growth factor receptor alpha (PDGFRA)	OTDJXUCN	PGFRA_HUMAN	Decreases Expression	[10]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[10]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[10]
Protein patched homolog 1 (PTCH1)	OTMG07H5	PTC1_HUMAN	Decreases Expression	[10]
Protein smoothened (SMO)	OTXXE208	SMO_HUMAN	Decreases Expression	[10]
Protein patched homolog 2 (PTCH2)	OTOQ0K9V	PTC2_HUMAN	Decreases Expression	[10]
Suppressor of fused homolog (SUFU)	OT0IRYG1	SUFU_HUMAN	Decreases Response To Substance	[11]
N-myc proto-oncogene protein (MYCN)	OTWD33K1	MYCN_HUMAN	Decreases Response To Substance	[11]

Indication(s) of Taxol

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Approved	[4]
Solid tumour/cancer	2A00-2F9Z	Approved	[5]
Pancreatic cancer	2C10	Phase 3	[6]
Gastric adenocarcinoma	2B72	Phase 2	[7]
Ovarian cancer	2C73	Phase 2	[7]

Taxol Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Apoptosis regulator Bcl-2 (BCL-2)	TTJGNVC	BCL2_HUMAN	Modulator	[4]
Tubulin beta (TUBB)	TTYFKSZ	NOUNIPROTAC	Modulator	[4]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Carcinoma	DCIOAR4	RXF 393	Investigative	[1]
Invasive ductal carcinoma	DCT1U19	T-47D	Investigative	[1]
Adenocarcinoma	DC3J5K7	DU-145	Investigative	[12]
Adenocarcinoma	DCS85A2	OVCAR3	Investigative	[12]
Adenocarcinoma	DCZ3JZA	A549	Investigative	[12]
Adenocarcinoma	DCD9YXM	NCIH23	Investigative	[12]
Adenocarcinoma	DCBWQJV	HCC-2998	Investigative	[12]
Adenocarcinoma	DCC6WN3	HT29	Investigative	[12]
Adult acute myeloid leukemia	DC5EE3V	HL-60(TB)	Investigative	[12]
Adult T acute lymphoblastic leukemia	DC8VG2G	MOLT-4	Investigative	[12]
Childhood T acute lymphoblastic leukemia	DCOGTC0	CCRF-CEM	Investigative	[12]
Clear cell renal cell carcinoma	DCLLGDK	A498	Investigative	[12]
Clear cell renal cell carcinoma	DCB714H	786-0	Investigative	[12]
Glioma	DCGGFT5	SF-295	Investigative	[12]
High grade ovarian serous adenocarcinoma	DCN12PT	OVCAR-5	Investigative	[12]
Lung adenocarcinoma	DC5WHS4	MDA-MB-231	Investigative	[12]
Lung adenocarcinoma	DCJZOYV	NCI-H522	Investigative	[12]
Malignant melanoma	DCLNUVJ	LOX IMVI	Investigative	[12]
Malignant melanoma	DCZNP4M	UACC62	Investigative	[12]
Minimally invasive lung adenocarcinoma	DCA0GAZ	NCI-H322M	Investigative	[12]
Mixed endometrioid and clear cell carcinoma	DCQYP0A	IGROV1	Investigative	[12]
Pleural epithelioid mesothelioma	DCUAIQH	NCI-H226	Investigative	[12]
Prostate carcinoma	DC67CKO	PC-3	Investigative	[12]

References

• [1] 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.
• [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] Paclitaxel directly binds to Bcl-2 and functionally mimics activity of Nur77. Cancer Res. 2009 Sep 1;69(17):6906-14.
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
• [9] The dawn of hedgehog inhibitors: Vismodegib. J Pharmacol Pharmacother. 2013 Jan;4(1):4-7.
• [10] 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.
• [11] 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.
• [12] 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.