Details of the Drug Combination

General Information of Drug Combination (ID: DCJY3GB)

• Drug Combination Name: Sirolimus + Bendamustine hydrochloride
• Indication: Pleural epithelioid mesothelioma; Status: Investigative [1]
• Component Drugs:
  Sirolimus (DMGW1ID): Small molecular drug
  Bendamustine hydrochloride (DMFH15Z): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: NCI-H226
  Zero Interaction Potency (ZIP) Score: 0.5
  Bliss Independence Score: 5.14
  Loewe Additivity Score: 2.86
  LHighest Single Agent (HSA) Score: 3.13

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Sirolimus

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

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	[9]
PI3K/AKT/mTOR pathway (PAm pathway)	TTGQUFK	NOUNIPROTAC	Inhibitor	[10]
HUMAN mammalian target of rapamycin (mTOR)	TT7HQAF	MTOR_HUMAN	Inhibitor	[11]

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	[12]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[13]

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	[14]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[15]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[15]

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	[16]
Calcineurin subunit B type 1 (PPP3R1)	OTGQNFJQ	CANB1_HUMAN	Increases ADR	[16]
Nuclear receptor ROR-gamma (RORC)	OTUBFRPC	RORG_HUMAN	Increases ADR	[16]

Indication(s) of Bendamustine hydrochloride

Disease Entry	ICD 11	Status	REF
leukaemia	2A60-2B33	Approved	[8]

Bendamustine hydrochloride Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human Deoxyribonucleic acid (hDNA)	TTUTN1I	NOUNIPROTAC	Modulator	[8]

Bendamustine hydrochloride Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[18]

Bendamustine hydrochloride Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[17]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[17]
Beta-galactosidase (GLB1)	OTB0TKAG	BGAL_HUMAN	Increases Expression	[19]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[17]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[17]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[17]
Caspase-6 (CASP6)	OTXLD3EC	CASP6_HUMAN	Increases Activity	[17]
Baculoviral IAP repeat-containing protein 3 (BIRC3)	OT3E95KB	BIRC3_HUMAN	Decreases Expression	[17]
Baculoviral IAP repeat-containing protein 2 (BIRC2)	OTFXFREP	BIRC2_HUMAN	Decreases Expression	[20]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[17]
PRKC apoptosis WT1 regulator protein (PAWR)	OTKY7W52	PAWR_HUMAN	Decreases Expression	[17]
Diablo IAP-binding mitochondrial protein (DIABLO)	OTHJ9MCZ	DBLOH_HUMAN	Increases Localization	[17]
Death domain-associated protein 6 (DAXX)	OTX6O7PL	DAXX_HUMAN	Decreases Expression	[17]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adenocarcinoma	DCA06DW	HCT-15	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] Sirolimus FDA Label
• [3] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (ANDA) 201578.
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] 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).
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] ClinicalTrials.gov (NCT04341675) Sirolimus Treatment in Hospitalized Patients With COVID-19 Pneumonia. U.S. National Institutes of Health.
• [8] 2008 FDA drug approvals. Nat Rev Drug Discov. 2009 Feb;8(2):93-6.
• [9] Knockouts model the 100 best-selling drugs--will they model the next 100 Nat Rev Drug Discov. 2003 Jan;2(1):38-51.
• [10] The genomic landscape of nasopharyngeal carcinoma.Nat Genet. 2014 Aug;46(8):866-71.
• [11] Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov. 2020 Mar 16;6:14.
• [12] Pharmacogenetics of tacrolimus and sirolimus in renal transplant patients: from retrospective analyses to prospective studies. Transplant Proc. 2007 Sep;39(7):2142-4.
• [13] 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.
• [14] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [15] Drug Interactions Flockhart Table
• [16] 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.
• [17] Synergistic effects of chemotherapeutic drugs in lymphoma cells are associated with down-regulation of inhibitor of apoptosis proteins (IAPs), prostate-apoptosis-response-gene 4 (Par-4), death-associated protein (Daxx) and with enforced caspase activation. Biochem Pharmacol. 2003 Sep 1;66(5):711-24. doi: 10.1016/s0006-2952(03)00410-6.
• [18] Pharmacokinetic and pharmacodynamic profile of bendamustine and its metabolites. Cancer Chemother Pharmacol. 2015 Jun;75(6):1143-54.
• [19] Chronic senescent human mesenchymal stem cells as possible contributor to the wound healing disorder after exposure to the alkylating agent sulfur mustard. Arch Toxicol. 2021 Feb;95(2):727-747. doi: 10.1007/s00204-020-02946-5. Epub 2021 Jan 25.
• [20] Upon drug-induced apoptosis in lymphoma cells X-linked inhibitor of apoptosis (XIAP) translocates from the cytosol to the nucleus. Leuk Lymphoma. 2004 Jul;45(7):1429-36. doi: 10.1080/1042819042000198858.