Details of the Drug Combination

General Information of Drug Combination (ID: DC23FJP)

Drug Combination Name

Vemurafenib Sirolimus

Indication

Disease Entry	Status	REF
Clear cell renal cell carcinoma	Investigative	[1]

Component Drugs

Vemurafenib DM62UG5

Sirolimus DMGW1ID

Small molecular drug

2D MOL

3D MOL

High-throughput Screening Result

Testing Cell Line: A498

Zero Interaction Potency (ZIP) Score: 6.83

Bliss Independence Score: 13.42

Loewe Additivity Score: 11.75

LHighest Single Agent (HSA) Score: 14.09

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)

Indication(s) of Vemurafenib

Disease Entry	ICD 11	Status	REF
Melanoma	2C30	Approved	[2]

Vemurafenib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Serine/threonine-protein kinase B-raf (BRAF)	TTWCGQT	BRAF_HUMAN	Modulator	[5]
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Vemurafenib Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[11]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[12]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[12]
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Vemurafenib Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[13]
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Vemurafenib Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Microphthalmia-associated transcription factor (MITF)	OT6XJCZH	MITF_HUMAN	Affects Expression	[9]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[14]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[15]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[10]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[10]
CD70 antigen (CD70)	OTHB2AL1	CD70_HUMAN	Decreases Expression	[16]
Melanocyte protein PMEL (PMEL)	OTCDDHHM	PMEL_HUMAN	Increases Expression	[9]
Melanoma antigen recognized by T-cells 1 (MLANA)	OT1N2S2K	MAR1_HUMAN	Increases Expression	[9]
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⏷ Show the Full List of 8 DOT(s)

Indication(s) of Sirolimus

Disease Entry	ICD 11	Status	REF
Advanced cancer	2A00-2F9Z	Approved	[3]
Brainstem neoplasm	N.A.	Approved	[3]
Graft-versus-host disease	4B24	Approved	[3]
Intracranial meningioma	N.A.	Approved	[3]
Lung cancer	2C25.0	Approved	[3]
Lung lymphangioleiomyomatosis	N.A.	Approved	[3]
Lymphangioleiomyomatosis	CB07	Approved	[4]
Mucosal melanoma	N.A.	Approved	[3]
Multiple myeloma	2A83	Approved	[5]
Multiple sclerosis	8A40	Approved	[3]
Non-small-cell lung cancer	2C25.Y	Approved	[3]
Organ transplant rejection	NE84	Approved	[6]
Plasma cell myeloma	2A83.1	Approved	[3]
Prostate cancer	2C82.0	Approved	[3]
Salivary gland squamous cell carcinoma	N.A.	Approved	[3]
Uveitis	9A96.Z	Phase 3	[7]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[8]
Dutch elm disease	8D64	Phase 1/2	[6]
Castration-resistant prostate carcinoma	N.A.	Investigative	[3]
Neuroblastoma	2D11.2	Investigative	[3]
Pancreatic acinar cell carcinoma	N.A.	Investigative	[3]
Polycystic kidney disease	GB8Y	Investigative	[3]
Rheumatoid arthritis	FA20	Investigative	[3]

Sirolimus Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Serine/threonine-protein kinase mTOR (mTOR)	TTCJG29	MTOR_HUMAN	Inhibitor	[17]
PI3K/AKT/mTOR pathway (PAm pathway)	TTGQUFK	NOUNIPROTAC	Inhibitor	[18]
HUMAN mammalian target of rapamycin (mTOR)	TT7HQAF	MTOR_HUMAN	Inhibitor	[19]
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Sirolimus Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[20]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[21]
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Sirolimus Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[22]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[23]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[23]
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Sirolimus Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Calcineurin subunit B type 1 (PPP3R1)	OTGQNFJQ	CANB1_HUMAN	Increases ADR	[24]
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Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Breast adenocarcinoma	DC3GK5T	MDA-MB-468	Investigative	[25]
Carcinoma	DC4EIN7	RXF 393	Investigative	[25]
Colon adenocarcinoma	DCIUX4O	COLO 205	Investigative	[25]
Colon carcinoma	DCX6ZOG	KM12	Investigative	[25]
Invasive ductal carcinoma	DCCKC4S	T-47D	Investigative	[25]
Invasive ductal carcinoma	DC3FEP3	HS 578T	Investigative	[25]
Amelanotic melanoma	DCI4L77	M14	Investigative	[1]
Amelanotic melanoma	DC9GAAC	MDA-MB-435	Investigative	[1]
Anaplastic large cell lymphoma	DCTACOE	SR	Investigative	[1]
Astrocytoma	DC15YFY	U251	Investigative	[1]
Clear cell renal cell carcinoma	DCB8G8P	786-0	Investigative	[1]
Clear cell renal cell carcinoma	DCCQXLI	TK-10	Investigative	[1]
Clear cell renal cell carcinoma	DCM492V	CAKI-1	Investigative	[1]
Cutaneous melanoma	DCK6GE5	SK-MEL-28	Investigative	[1]
Cutaneous melanoma	DC3PF7Z	SK-MEL-5	Investigative	[1]
Malignant melanoma	DCC1N6T	LOX IMVI	Investigative	[1]
Melanoma	DCNOFM3	MALME-3M	Investigative	[1]
Melanoma	DCOBAGD	UACC-257	Investigative	[1]
Mixed endometrioid and clear cell carcinoma	DC59RVX	IGROV1	Investigative	[1]
Papillary renal cell carcinoma	DCUK71T	ACHN	Investigative	[1]
Pleural epithelioid mesothelioma	DCRMUNX	NCI-H226	Investigative	[1]
Renal cell carcinoma	DC8TNUI	UO-31	Investigative	[1]
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⏷ Show the Full List of 22 DrugCom(s)

References

1	CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125976
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: 5893).
3	Sirolimus FDA Label
4	FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (ANDA) 201578.
5	Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
6	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: 6031).
7	Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
8	ClinicalTrials.gov (NCT04341675) Sirolimus Treatment in Hospitalized Patients With COVID-19 Pneumonia. U.S. National Institutes of Health.
9	PLX4032 Mediated Melanoma Associated Antigen Potentiation in Patient Derived Primary Melanoma Cells. J Cancer. 2015 Oct 29;6(12):1320-30. doi: 10.7150/jca.11126. eCollection 2015.
10	Actin remodeling confers BRAF inhibitor resistance to melanoma cells through YAP/TAZ activation. EMBO J. 2016 Mar 1;35(5):462-78. doi: 10.15252/embj.201592081. Epub 2015 Dec 14.
11	Differential effects of the oncogenic BRAF inhibitor PLX4032 (vemurafenib) and its progenitor PLX4720 on ABCB1 function. J Pharm Pharm Sci. 2014;17(1):154-68.
12	Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013 Mar 15;19(6):1458-66.
13	Vemurafenib for the treatment of melanoma. Expert Opin Pharmacother. 2012 Dec;13(17):2533-43.
14	Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells. Elife. 2015 Aug 18;4:e04640. doi: 10.7554/eLife.04640.
15	Overcoming melanoma resistance to vemurafenib by targeting CCL2-induced miR-34a, miR-100 and miR-125b. Oncotarget. 2016 Jan 26;7(4):4428-41. doi: 10.18632/oncotarget.6599.
16	Melanoma Expressed-CD70 Is Regulated by RhoA and MAPK Pathways without Affecting Vemurafenib Treatment Activity. PLoS One. 2016 Feb 1;11(2):e0148095. doi: 10.1371/journal.pone.0148095. eCollection 2016.
17	Knockouts model the 100 best-selling drugs--will they model the next 100 Nat Rev Drug Discov. 2003 Jan;2(1):38-51.
18	The genomic landscape of nasopharyngeal carcinoma.Nat Genet. 2014 Aug;46(8):866-71.
19	Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov. 2020 Mar 16;6:14.
20	Pharmacogenetics of tacrolimus and sirolimus in renal transplant patients: from retrospective analyses to prospective studies. Transplant Proc. 2007 Sep;39(7):2142-4.
21	Pharmacokinetic and pharmacodynamic interactions between the immunosuppressant sirolimus and the lipid-lowering drug ezetimibe in healthy volunteers. Clin Pharmacol Ther. 2010 Jun;87(6):663-7.
22	Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
23	Drug Interactions Flockhart Table
24	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.
25	CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1126165