Details of the Drug Combination

General Information of Drug Combination (ID: DCX7L08)

• Drug Combination Name: Plicamycin + Sirolimus
• Indication: Renal cell carcinoma; Status: Investigative [1]
• Component Drugs:
  Plicamycin (DM7C8YV): Small molecular drug
  Sirolimus (DMGW1ID): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: UO-31
  Zero Interaction Potency (ZIP) Score: 3.29
  Bliss Independence Score: 3.91
  Loewe Additivity Score: 2.41
  LHighest Single Agent (HSA) Score: 4.83

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Plicamycin

Disease Entry	ICD 11	Status	REF
Hypercalcaemia	5B91.0	Approved	[2]
Testicular cancer	2C80	Approved	[2]
Solid tumour/cancer	2A00-2F9Z	Withdrawn from market	[3]
Lung cancer	2C25.0	Investigative	[4]
Ovarian cancer	2C73	Investigative	[4]

Plicamycin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
RNA synthesis (hRNA synth)	TTX2AYW	NOUNIPROTAC	Modulator	[11]

Plicamycin Interacts with 16 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	[12]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Expression	[13]
Aryl hydrocarbon receptor (AHR)	OTFE4EYE	AHR_HUMAN	Decreases Expression	[13]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Expression	[13]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[14]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Activity	[14]
Epoxide hydrolase 1 (EPHX1)	OTBKWQER	HYEP_HUMAN	Decreases Expression	[15]
Transcription factor Sp1 (SP1)	OTISPT4X	SP1_HUMAN	Decreases Expression	[10]
Proto-oncogene tyrosine-protein kinase Src (SRC)	OTETYX40	SRC_HUMAN	Decreases Expression	[16]
Tissue factor (F3)	OT3MSU3B	TF_HUMAN	Decreases Expression	[17]
Tyrosine-protein kinase receptor UFO (AXL)	OTKA2SUX	UFO_HUMAN	Decreases Expression	[18]
Transcription factor Sp3 (SP3)	OTYDQZ1T	SP3_HUMAN	Decreases Expression	[10]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[19]
Epidermal growth factor receptor kinase substrate 8 (EPS8)	OTZ6ES6V	EPS8_HUMAN	Decreases Expression	[16]
TNFAIP3-interacting protein 1 (TNIP1)	OTRAOTEW	TNIP1_HUMAN	Decreases Expression	[20]
Sphingomyelin phosphodiesterase 3 (SMPD3)	OTHQBETH	NSMA2_HUMAN	Decreases Expression	[21]

Indication(s) of Sirolimus

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

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	[22]
PI3K/AKT/mTOR pathway (PAm pathway)	TTGQUFK	NOUNIPROTAC	Inhibitor	[23]
HUMAN mammalian target of rapamycin (mTOR)	TT7HQAF	MTOR_HUMAN	Inhibitor	[24]

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	[25]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[26]

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	[27]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[28]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[28]

Sirolimus Interacts with 3 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Interleukin-2 (IL2)	OTGI4NSA	IL2_HUMAN	Increases ADR	[29]
Calcineurin subunit B type 1 (PPP3R1)	OTGQNFJQ	CANB1_HUMAN	Increases ADR	[29]
Nuclear receptor ROR-gamma (RORC)	OTUBFRPC	RORG_HUMAN	Increases ADR	[29]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Astrocytoma	DC293BQ	U251	Investigative	[1]
Glioma	DC4JTGU	SF-539	Investigative	[1]
Glioma	DC3CFFS	SF-268	Investigative	[1]
Plasma cell myeloma	DCCBX8F	RPMI-8226	Investigative	[1]
Breast adenocarcinoma	DC733JO	MDA-MB-468	Investigative	[30]
Cutaneous melanoma	DCR5UCP	SK-MEL-5	Investigative	[31]
High grade ovarian serous adenocarcinoma	DCOGK6P	OVCAR-4	Investigative	[31]
High grade ovarian serous adenocarcinoma	DCE2WCT	OVCAR-8	Investigative	[31]
High grade ovarian serous adenocarcinoma	DCG4464	NCI\\/ADR-RES	Investigative	[31]
Pleural epithelioid mesothelioma	DCPGRHR	NCI-H226	Investigative	[31]
Prostate carcinoma	DCLSJIB	PC-3	Investigative	[31]

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] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [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: 8394).
• [4] The Pluripotency Factor Musashi-2 Is a Novel Target for Lung Cancer Therapy.Ann Am Thorac Soc. 2018 Apr;15(Supplement_2):S124.
• [5] Sirolimus FDA Label
• [6] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (ANDA) 201578.
• [7] 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).
• [8] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [9] ClinicalTrials.gov (NCT04341675) Sirolimus Treatment in Hospitalized Patients With COVID-19 Pneumonia. U.S. National Institutes of Health.
• [10] 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.
• [11] Role of magnesium ion in mithramycin-DNA interaction: binding of mithramycin-Mg2+ complexes with DNA. Biochemistry. 1995 Jan 31;34(4):1376-85.
• [12] 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.
• [13] Metformin suppresses CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating aryl hydrocarbon receptor expression. Toxicol Appl Pharmacol. 2014 Oct 1;280(1):138-48.
• [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] Sp1 and Sp3 transcription factors regulate the basal expression of human microsomal epoxide hydrolase (EPHX1) through interaction with the E1b far upstream promoter. Gene. 2014 Feb 15;536(1):135-44. doi: 10.1016/j.gene.2013.11.053. Epub 2013 Dec 4.
• [16] 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.
• [17] Asbestos induces tissue factor in Beas-2B human lung bronchial epithelial cells in vitro. Lung. 2004;182(4):251-64. doi: 10.1007/s00408-004-2507-2.
• [18] 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.
• [19] CREB/Sp1-mediated MCL1 expression and NFB-mediated ABCB1 expression modulate the cytotoxicity of daunorubicin in chronic myeloid leukemia cells. Toxicol Appl Pharmacol. 2022 Jan 15;435:115847. doi: 10.1016/j.taap.2021.115847. Epub 2021 Dec 25.
• [20] 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.
• [21] 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.
• [22] Knockouts model the 100 best-selling drugs--will they model the next 100 Nat Rev Drug Discov. 2003 Jan;2(1):38-51.
• [23] The genomic landscape of nasopharyngeal carcinoma.Nat Genet. 2014 Aug;46(8):866-71.
• [24] Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov. 2020 Mar 16;6:14.
• [25] Pharmacogenetics of tacrolimus and sirolimus in renal transplant patients: from retrospective analyses to prospective studies. Transplant Proc. 2007 Sep;39(7):2142-4.
• [26] 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.
• [27] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [28] Drug Interactions Flockhart Table
• [29] 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.
• [30] 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.
• [31] 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.