Details of the Drug Combination

General Information of Drug Combination (ID: DCOWO9T)

• Drug Combination Name: Ruxolitinib + Vismodegib
• Indication: Clear cell renal cell carcinoma; Status: Investigative [1]
• Component Drugs:
  Ruxolitinib (DM7Q98D): Small molecular drug
  Vismodegib (DM5IXKQ): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: CAKI-1
  Zero Interaction Potency (ZIP) Score: 2.48
  Bliss Independence Score: 6.7
  Loewe Additivity Score: 3.46
  LHighest Single Agent (HSA) Score: 8.05

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Ruxolitinib

Disease Entry	ICD 11	Status	REF
Essential thrombocythemia	3B63.1Z	Approved	[2]
High-risk myelofibrosis	2A20.2	Approved	[3]
Myelofibrosis	2A22	Approved	[4]
Myeloproliferative neoplasm	2A20	Approved	[5]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[6]
Pancreatic cancer	2C10	Phase 3	[3]
Atopic dermatitis	EA80	Phase 1/2	[7]
Vitiligo	ED63.0	Phase 1/2	[7]

Ruxolitinib Interacts with 5 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Janus kinase 2 (JAK-2)	TTRMX3V	JAK2_HUMAN	Modulator	[10]
Janus kinase 1 (JAK-1)	TT6DM01	JAK1_HUMAN	Modulator	[10]
Urokinase plasminogen activator surface receptor (PLAUR)	TTPRL03	UPAR_HUMAN	Inhibitor	[11]
HUMAN janus kinase 1 (JAK-1)	TTWKB01	JAK1_HUMAN	Inhibitor	[12]
HUMAN janus kinase 2 (JAK-2)	TT0F5HE	JAK2_HUMAN	Inhibitor	[12]

Ruxolitinib Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Mitogen-activated protein kinase 14 (MAPK14)	OT5TCO3O	MK14_HUMAN	Increases ADR	[13]

Indication(s) of Vismodegib

Disease Entry	ICD 11	Status	REF
Basal cell carcinoma	2C32	Approved	[8]
Primitive neuroectodermal tumour medulloblastoma	2A00.11	Phase 2	[9]

Vismodegib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Smoothened homolog (SMO)	TT8J1S3	SMO_HUMAN	Modulator	[14]

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	[15]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[15]

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	[16]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[16]
Zinc finger protein GLI1 (GLI1)	OT1BTAJO	GLI1_HUMAN	Decreases Expression	[16]
Zinc finger protein GLI2 (GLI2)	OTIRV97L	GLI2_HUMAN	Decreases Expression	[16]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[16]
Platelet-derived growth factor receptor alpha (PDGFRA)	OTDJXUCN	PGFRA_HUMAN	Decreases Expression	[16]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[16]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[16]
Protein patched homolog 1 (PTCH1)	OTMG07H5	PTC1_HUMAN	Decreases Expression	[16]
Protein smoothened (SMO)	OTXXE208	SMO_HUMAN	Decreases Expression	[16]
Protein patched homolog 2 (PTCH2)	OTOQ0K9V	PTC2_HUMAN	Decreases Expression	[16]
Suppressor of fused homolog (SUFU)	OT0IRYG1	SUFU_HUMAN	Decreases Response To Substance	[17]
N-myc proto-oncogene protein (MYCN)	OTWD33K1	MYCN_HUMAN	Decreases Response To Substance	[17]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Myelofibrosis	DC1GME1	N. A.	Phase 1	[18]
Plasma cell myeloma	DCW8GW4	RPMI-8226	Investigative	[1]
Breast adenocarcinoma	DCC6H2Y	MDA-MB-468	Investigative	[19]
Invasive ductal carcinoma	DC609OR	HS 578T	Investigative	[19]
Melanoma	DCXN6ZR	SK-MEL-2	Investigative	[20]

References

• [1] Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] 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: 5688).
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] Ruxolitinib FDA Label
• [6] Incyte begins Phase III trial of ruxolitinib to treat Covid-19. 20.April.2020.
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] 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).
• [9] 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.
• [10] 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
• [11] Urokinase-type plasminogen activator receptor signaling is critical in nasopharyngeal carcinoma cell growth and metastasis.Cell Cycle. 2014;13(12):1958-69.
• [12] The Use of Anti-Inflammatory Drugs in the Treatment of People With Severe Coronavirus Disease 2019 (COVID-19): The Perspectives of Clinical Immunologists From China. Clin Immunol. 2020 May;214:108393.
• [13] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [14] Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
• [15] The dawn of hedgehog inhibitors: Vismodegib. J Pharmacol Pharmacother. 2013 Jan;4(1):4-7.
• [16] 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.
• [17] 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.
• [18] ClinicalTrials.gov (NCT02593760) A Study to Evaluate the Efficacy and Safety of Vismodegib in Combination With Ruxolitinib for the Treatment of Intermediate- or High-Risk Myelofibrosis (MF)
• [19] 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.
• [20] 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.