Details of the Drug Combination

General Information of Drug Combination (ID: DCDUCJA)

• Drug Combination Name: ABIRATERONE + Sirolimus
• Indication: Malignant melanoma; Status: Investigative [1]
• Component Drugs:
  ABIRATERONE (DM8V75C): Small molecular drug
  Sirolimus (DMGW1ID): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: LOX IMVI
  Zero Interaction Potency (ZIP) Score: 14.63
  Bliss Independence Score: 13.6
  Loewe Additivity Score: 17.24
  LHighest Single Agent (HSA) Score: 18.12

Molecular Interaction Atlas of This Drug Combination

Indication(s) of ABIRATERONE

Disease Entry	ICD 11	Status	REF
Prostate cancer	2C82.0	Approved	[2]

ABIRATERONE Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Steroid 17-alpha-monooxygenase (S17AH)	TTRA5BZ	CP17A_HUMAN	Modulator	[9]

ABIRATERONE Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1)	OTZKVLVJ	CP17A_HUMAN	Decreases Activity	[10]
Tissue factor (F3)	OT3MSU3B	TF_HUMAN	Increases Expression	[11]
Membrane cofactor protein (CD46)	OTQ8NWJD	MCP_HUMAN	Increases Expression	[12]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Decreases Response To Substance	[13]

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	[14]
PI3K/AKT/mTOR pathway (PAm pathway)	TTGQUFK	NOUNIPROTAC	Inhibitor	[15]
HUMAN mammalian target of rapamycin (mTOR)	TT7HQAF	MTOR_HUMAN	Inhibitor	[16]

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	[17]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[18]

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	[19]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[20]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[20]

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	[21]
Calcineurin subunit B type 1 (PPP3R1)	OTGQNFJQ	CANB1_HUMAN	Increases ADR	[21]
Nuclear receptor ROR-gamma (RORC)	OTUBFRPC	RORG_HUMAN	Increases ADR	[21]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adult T acute lymphoblastic leukemia	DCRHQMW	MOLT-4	Investigative	[22]
Anaplastic large cell lymphoma	DCT44AK	SR	Investigative	[22]
Astrocytoma	DCLX2FC	U251	Investigative	[22]
Astrocytoma	DCXJN9I	SNB-19	Investigative	[22]
Childhood T acute lymphoblastic leukemia	DCHQEWA	CCRF-CEM	Investigative	[22]
Clear cell renal cell carcinoma	DCI1M34	786-0	Investigative	[22]
Clear cell renal cell carcinoma	DCHII5R	TK-10	Investigative	[22]
Plasma cell myeloma	DC9MMQT	RPMI-8226	Investigative	[22]
Renal cell carcinoma	DCSXYW4	UO-31	Investigative	[22]
Breast adenocarcinoma	DC2C5DK	MDA-MB-468	Investigative	[23]
Carcinoma	DCF33KO	MCF7	Investigative	[23]
Colon carcinoma	DC28YHQ	KM12	Investigative	[23]
Invasive ductal carcinoma	DCJOVC6	HS 578T	Investigative	[23]
Adenocarcinoma	DCFXF77	OVCAR3	Investigative	[1]
Adenocarcinoma	DCB8PHP	A549	Investigative	[1]
Adenocarcinoma	DCGEUGE	HT29	Investigative	[1]
Adenocarcinoma	DCWXSQC	HCT116	Investigative	[1]
Adenocarcinoma	DCQKCAW	HCC-2998	Investigative	[1]
Adenocarcinoma	DC0J3S4	HCT-15	Investigative	[1]
Adenocarcinoma	DCCGGT0	SW-620	Investigative	[1]
Amelanotic melanoma	DC1LCIN	MDA-MB-435	Investigative	[1]
Cutaneous melanoma	DCZB25I	SK-MEL-28	Investigative	[1]
Large cell lung carcinoma	DC0GRMS	NCI-H460	Investigative	[1]
Lung adenocarcinoma	DCX7QV2	HOP-62	Investigative	[1]
Lung adenocarcinoma	DC3E7MM	MDA-MB-231	Investigative	[1]
Lung adenocarcinoma	DC44BU7	NCI-H522	Investigative	[1]
Malignant melanoma	DC2E5H6	UACC62	Investigative	[1]
Melanoma	DCEH1XV	MALME-3M	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] 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: 6745).
• [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] 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
• [10] A fission yeast-based test system for the determination of IC50 values of anti-prostate tumor drugs acting on CYP21. J Enzyme Inhib Med Chem. 2006 Oct;21(5):547-56.
• [11] Elucidating mechanisms of toxicity using phenotypic data from primary human cell systems--a chemical biology approach for thrombosis-related side effects. Int J Mol Sci. 2015 Jan 5;16(1):1008-29. doi: 10.3390/ijms16011008.
• [12] Targeting CD46 for both adenocarcinoma and neuroendocrine prostate cancer. JCI Insight. 2018 Sep 6;3(17):e121497. doi: 10.1172/jci.insight.121497. eCollection 2018 Sep 6.
• [13] Targeting chromatin binding regulation of constitutively active AR variants to overcome prostate cancer resistance to endocrine-based therapies. Nucleic Acids Res. 2015 Jul 13;43(12):5880-97. doi: 10.1093/nar/gkv262. Epub 2015 Apr 23.
• [14] Knockouts model the 100 best-selling drugs--will they model the next 100 Nat Rev Drug Discov. 2003 Jan;2(1):38-51.
• [15] The genomic landscape of nasopharyngeal carcinoma.Nat Genet. 2014 Aug;46(8):866-71.
• [16] Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov. 2020 Mar 16;6:14.
• [17] Pharmacogenetics of tacrolimus and sirolimus in renal transplant patients: from retrospective analyses to prospective studies. Transplant Proc. 2007 Sep;39(7):2142-4.
• [18] 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.
• [19] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [20] Drug Interactions Flockhart Table
• [21] 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.
• [22] 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.
• [23] 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.