Details of the Drug Combination

General Information of Drug Combination (ID: DC8MTTI)

• Drug Combination Name: Vismodegib + Cabazitaxel
• Indication: Clear cell renal cell carcinoma; Status: Investigative [1]
• Component Drugs:
  Vismodegib (DM5IXKQ): Small molecular drug
  Cabazitaxel (DMPAZHC): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: TK-10
  Zero Interaction Potency (ZIP) Score: 8.36
  Bliss Independence Score: 8.55
  Loewe Additivity Score: 7.45
  LHighest Single Agent (HSA) Score: 9.66

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	[6]

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	[7]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[7]

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	[8]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[8]
Zinc finger protein GLI1 (GLI1)	OT1BTAJO	GLI1_HUMAN	Decreases Expression	[8]
Zinc finger protein GLI2 (GLI2)	OTIRV97L	GLI2_HUMAN	Decreases Expression	[8]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[8]
Platelet-derived growth factor receptor alpha (PDGFRA)	OTDJXUCN	PGFRA_HUMAN	Decreases Expression	[8]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[8]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[8]
Protein patched homolog 1 (PTCH1)	OTMG07H5	PTC1_HUMAN	Decreases Expression	[8]
Protein smoothened (SMO)	OTXXE208	SMO_HUMAN	Decreases Expression	[8]
Protein patched homolog 2 (PTCH2)	OTOQ0K9V	PTC2_HUMAN	Decreases Expression	[8]
Suppressor of fused homolog (SUFU)	OT0IRYG1	SUFU_HUMAN	Decreases Response To Substance	[9]
N-myc proto-oncogene protein (MYCN)	OTWD33K1	MYCN_HUMAN	Decreases Response To Substance	[9]

Indication(s) of Cabazitaxel

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Approved	[4]
Solid tumour/cancer	2A00-2F9Z	Phase 2	[4]
Metastatic prostate carcinoma	N.A.	Investigative	[5]

Cabazitaxel Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Tubulin (TUB)	TTML2WA	NOUNIPROTAC	Inhibitor	[10]

Cabazitaxel Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[11]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[11]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[11]

Cabazitaxel Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Forkhead box protein O3 (FOXO3)	OTHXQG4P	FOXO3_HUMAN	Affects Expression	[12]
Proline-rich AKT1 substrate 1 (AKT1S1)	OT4JHN4Y	AKTS1_HUMAN	Decreases Expression	[12]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Breast adenocarcinoma	DC0TA9G	MDA-MB-468	Investigative	[13]
Carcinoma	DC4O6V2	MCF7	Investigative	[13]
Invasive ductal carcinoma	DC8Q18T	T-47D	Investigative	[13]
Invasive ductal carcinoma	DC8HJMD	BT-549	Investigative	[13]
Adenocarcinoma	DCRQROH	DU-145	Investigative	[1]
Adenocarcinoma	DCFFKW4	OVCAR3	Investigative	[1]
Adenocarcinoma	DCTWHGN	NCIH23	Investigative	[1]
Adenocarcinoma	DCYLJFJ	A549	Investigative	[1]
Adenocarcinoma	DC1PNEM	HCT-15	Investigative	[1]
Adenocarcinoma	DCJS2E2	HCC-2998	Investigative	[1]
Adenocarcinoma	DCELR9M	HCT116	Investigative	[1]
Adenocarcinoma	DCPLLTU	HT29	Investigative	[1]
Adult T acute lymphoblastic leukemia	DC1PLQM	MOLT-4	Investigative	[1]
Astrocytoma	DCGHIOA	U251	Investigative	[1]
Childhood T acute lymphoblastic leukemia	DCC2YPB	CCRF-CEM	Investigative	[1]
Chronic myelogenous leukemia	DC7CSIB	K-562	Investigative	[1]
Glioma	DCABDF7	SF-539	Investigative	[1]
Glioma	DCSN2RP	SF-295	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCFEOLK	OVCAR-4	Investigative	[1]
High grade ovarian serous adenocarcinoma	DC4GI6Z	OVCAR-8	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCRZWSL	NCI\\/ADR-RES	Investigative	[1]
Large cell lung carcinoma	DCYA89K	NCI-H460	Investigative	[1]
Lung adenocarcinoma	DCWQ3IU	MDA-MB-231	Investigative	[1]
Lung adenocarcinoma	DCSPK1S	EKVX	Investigative	[1]
Lung adenocarcinoma	DCUSMF0	HOP-62	Investigative	[1]
Lung adenocarcinoma	DCX601H	NCI-H522	Investigative	[1]
Malignant melanoma	DCWM7EB	UACC62	Investigative	[1]
Melanoma	DCQU74P	MALME-3M	Investigative	[1]
Minimally invasive lung adenocarcinoma	DCX8XBY	NCI-H322M	Investigative	[1]
Mixed endometrioid and clear cell carcinoma	DCA2CJA	IGROV1	Investigative	[1]
Non-small cell lung carcinoma	DC7GVQ9	HOP-92	Investigative	[1]
Ovarian serous cystadenocarcinoma	DCSCQXJ	SK-OV-3	Investigative	[1]
Pleural epithelioid mesothelioma	DCP2XU8	NCI-H226	Investigative	[1]
Prostate carcinoma	DC0Z8ZQ	PC-3	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] 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: 6798).
• [5] Cabazitaxel FDA Label
• [6] Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
• [7] The dawn of hedgehog inhibitors: Vismodegib. J Pharmacol Pharmacother. 2013 Jan;4(1):4-7.
• [8] 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.
• [9] 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.
• [10] Mullard A: 2010 FDA drug approvals. Nat Rev Drug Discov. 2011 Feb;10(2):82-5.
• [11] DAILYMED.nlm.nih.gov: JEVTANA- cabazitaxel kit.
• [12] The triphenyltin carboxylate derivative triphenylstannyl 2-(benzylcarbamoyl)benzoate impedes prostate cancer progression via modulation of Akt/FOXO3a signaling. Toxicol Appl Pharmacol. 2020 Aug 15;401:115091. doi: 10.1016/j.taap.2020.115091. Epub 2020 Jun 7.
• [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.