Details of the Drug Combination

General Information of Drug Combination (ID: DCHS59M)

• Drug Combination Name: Cabazitaxel + Sirolimus
• Indication: Clear cell renal cell carcinoma; Status: Investigative [1]
• Component Drugs:
  Cabazitaxel (DMPAZHC): Small molecular drug
  Sirolimus (DMGW1ID): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: A498
  Zero Interaction Potency (ZIP) Score: 0.32
  Bliss Independence Score: 3.01
  Loewe Additivity Score: 9.1
  LHighest Single Agent (HSA) Score: 11.3

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Cabazitaxel

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Approved	[2]
Solid tumour/cancer	2A00-2F9Z	Phase 2	[2]
Metastatic prostate carcinoma	N.A.	Investigative	[3]

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]

Indication(s) of Sirolimus

Disease Entry	ICD 11	Status	REF
Advanced cancer	2A00-2F9Z	Approved	[4]
Brainstem neoplasm	N.A.	Approved	[4]
Graft-versus-host disease	4B24	Approved	[4]
Intracranial meningioma	N.A.	Approved	[4]
Lung cancer	2C25.0	Approved	[4]
Lung lymphangioleiomyomatosis	N.A.	Approved	[4]
Lymphangioleiomyomatosis	CB07	Approved	[5]
Mucosal melanoma	N.A.	Approved	[4]
Multiple myeloma	2A83	Approved	[6]
Multiple sclerosis	8A40	Approved	[4]
Non-small-cell lung cancer	2C25.Y	Approved	[4]
Organ transplant rejection	NE84	Approved	[7]
Plasma cell myeloma	2A83.1	Approved	[4]
Prostate cancer	2C82.0	Approved	[4]
Salivary gland squamous cell carcinoma	N.A.	Approved	[4]
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	[4]
Neuroblastoma	2D11.2	Investigative	[4]
Pancreatic acinar cell carcinoma	N.A.	Investigative	[4]
Polycystic kidney disease	GB8Y	Investigative	[4]
Rheumatoid arthritis	FA20	Investigative	[4]

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	[13]
PI3K/AKT/mTOR pathway (PAm pathway)	TTGQUFK	NOUNIPROTAC	Inhibitor	[14]
HUMAN mammalian target of rapamycin (mTOR)	TT7HQAF	MTOR_HUMAN	Inhibitor	[15]

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	[16]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[17]

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	[18]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[19]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[19]

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	[20]
Calcineurin subunit B type 1 (PPP3R1)	OTGQNFJQ	CANB1_HUMAN	Increases ADR	[20]
Nuclear receptor ROR-gamma (RORC)	OTUBFRPC	RORG_HUMAN	Increases ADR	[20]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adenocarcinoma	DC0THID	DU-145	Investigative	[1]
Adenocarcinoma	DCP73KR	OVCAR3	Investigative	[1]
Adenocarcinoma	DCQLNK0	A549	Investigative	[1]
Adenocarcinoma	DCNIOBO	HCC-2998	Investigative	[1]
Adenocarcinoma	DCAJVX3	HCT-15	Investigative	[1]
Adenocarcinoma	DC6C03Q	HCT116	Investigative	[1]
Adenocarcinoma	DC4K83U	HT29	Investigative	[1]
Adult acute myeloid leukemia	DCVCLH7	HL-60(TB)	Investigative	[1]
Adult T acute lymphoblastic leukemia	DCMHW3R	MOLT-4	Investigative	[1]
Amelanotic melanoma	DC3V8NQ	MDA-MB-435	Investigative	[1]
Anaplastic large cell lymphoma	DCBG2ZH	SR	Investigative	[1]
Astrocytoma	DC25YED	U251	Investigative	[1]
Astrocytoma	DCPLH16	SNB-19	Investigative	[1]
Childhood T acute lymphoblastic leukemia	DCJ1VVO	CCRF-CEM	Investigative	[1]
Clear cell renal cell carcinoma	DCDWMOT	786-0	Investigative	[1]
Cutaneous melanoma	DCDEOE4	SK-MEL-5	Investigative	[1]
Glioblastoma	DC30CXZ	SNB-75	Investigative	[1]
Glioma	DC33X8K	SF-539	Investigative	[1]
Glioma	DCG2KYM	SF-295	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCC9FTL	OVCAR-4	Investigative	[1]
Large cell lung carcinoma	DCWQ0Y2	NCI-H460	Investigative	[1]
Lung adenocarcinoma	DC3SRH1	MDA-MB-231	Investigative	[1]
Lung adenocarcinoma	DCK7A1Y	NCI-H522	Investigative	[1]
Malignant melanoma	DCDAQNU	UACC62	Investigative	[1]
Malignant melanoma	DCPAUWH	LOX IMVI	Investigative	[1]
Melanoma	DCEUVHD	UACC-257	Investigative	[1]
Minimally invasive lung adenocarcinoma	DC5M5MZ	NCI-H322M	Investigative	[1]
Mixed endometrioid and clear cell carcinoma	DCJMFP4	IGROV1	Investigative	[1]
Non-small cell lung carcinoma	DC3CG3E	HOP-92	Investigative	[1]
Ovarian serous cystadenocarcinoma	DCX1O4W	SK-OV-3	Investigative	[1]
Papillary renal cell carcinoma	DCZMPRB	ACHN	Investigative	[1]
Plasma cell myeloma	DCT4T79	RPMI-8226	Investigative	[1]
Prostate carcinoma	DCHR28Y	PC-3	Investigative	[1]
Renal cell carcinoma	DCAFFM9	SN12C	Investigative	[1]
Renal cell carcinoma	DCDKG0V	UO-31	Investigative	[1]
Breast adenocarcinoma	DCVHIHW	MDA-MB-468	Investigative	[21]
Carcinoma	DC2XSNE	RXF 393	Investigative	[21]
Carcinoma	DC3JVOI	MCF7	Investigative	[21]
Colon adenocarcinoma	DCLAXWG	COLO 205	Investigative	[21]
Invasive ductal carcinoma	DC8WSO3	HS 578T	Investigative	[21]
Invasive ductal carcinoma	DCSWP21	T-47D	Investigative	[21]
Invasive ductal carcinoma	DCITP4O	BT-549	Investigative	[21]

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] 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).
• [3] Cabazitaxel FDA Label
• [4] Sirolimus FDA Label
• [5] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (ANDA) 201578.
• [6] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [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] 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] Knockouts model the 100 best-selling drugs--will they model the next 100 Nat Rev Drug Discov. 2003 Jan;2(1):38-51.
• [14] The genomic landscape of nasopharyngeal carcinoma.Nat Genet. 2014 Aug;46(8):866-71.
• [15] Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov. 2020 Mar 16;6:14.
• [16] Pharmacogenetics of tacrolimus and sirolimus in renal transplant patients: from retrospective analyses to prospective studies. Transplant Proc. 2007 Sep;39(7):2142-4.
• [17] 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.
• [18] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [19] Drug Interactions Flockhart Table
• [20] 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.
• [21] 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.