Details of the Drug Combination

General Information of Drug Combination (ID: DCOIC40)

• Drug Combination Name: Anastrozole + Sirolimus
• Indication: Cutaneous melanoma; Status: Investigative [1]
• Component Drugs:
  Anastrozole (DMNP60F): Small molecular drug
  Sirolimus (DMGW1ID): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: SK-MEL-28
  Zero Interaction Potency (ZIP) Score: 0.18
  Bliss Independence Score: 3.76
  Loewe Additivity Score: 6.74
  LHighest Single Agent (HSA) Score: 7.03

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Anastrozole

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Approved	[2]
Estrogen-receptor positive breast cancer	N.A.	Approved	[3]
Obesity	5B81	Approved	[3]

Anastrozole Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Aromatase (CYP19A1)	TTSZLWK	CP19A_HUMAN	Inhibitor	[10]

Anastrozole Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Putative sodium-coupled neutral amino acid transporter 7 (SLC38A7)	DT2EGUN	S38A7_HUMAN	Substrate	[11]

Anastrozole Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[12]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[12]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[12]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[12]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[12]
UDP-glucuronosyltransferase 1A3 (UGT1A3)	DEF2WXN	UD13_HUMAN	Metabolism	[12]

Anastrozole Interacts with 6 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Adenylate kinase isoenzyme 1 (AK1)	OT614AR3	KAD1_HUMAN	Increases ADR	[13]
Progesterone receptor (PGR)	OT0FZ3QE	PRGR_HUMAN	Decreases Expression	[14]
Aromatase (CYP19A1)	OTZ6XF74	CP19A_HUMAN	Decreases Activity	[15]
NADPH--cytochrome P450 reductase (POR)	OTVIDOCH	NCPR_HUMAN	Decreases Activity	[16]
Gap junction alpha-1 protein (GJA1)	OTT94MKL	CXA1_HUMAN	Decreases Expression	[17]
Proliferation marker protein Ki-67 (MKI67)	OTA8N1QI	KI67_HUMAN	Decreases Expression	[18]

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	[19]
PI3K/AKT/mTOR pathway (PAm pathway)	TTGQUFK	NOUNIPROTAC	Inhibitor	[20]
HUMAN mammalian target of rapamycin (mTOR)	TT7HQAF	MTOR_HUMAN	Inhibitor	[21]

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	[22]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[23]

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	[24]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[25]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[25]

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	[13]
Calcineurin subunit B type 1 (PPP3R1)	OTGQNFJQ	CANB1_HUMAN	Increases ADR	[13]
Nuclear receptor ROR-gamma (RORC)	OTUBFRPC	RORG_HUMAN	Increases ADR	[13]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adenocarcinoma	DCPW5WD	SW-620	Investigative	[1]
Amelanotic melanoma	DCUVMQQ	M14	Investigative	[1]
Glioblastoma	DCH0KTB	SNB-75	Investigative	[1]
Glioma	DCRG1N8	SF-268	Investigative	[1]

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: 5137).
• [3] Anastrozole 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] Effective aromatase inhibition by anastrozole in a patient with gonadotropin-independent precocious puberty in McCune-Albright syndrome. J Pediatr Endocrinol Metab. 2002;15 Suppl 3:945-8.
• [11] Anastrozole Aromatase Inhibitor Plasma Drug Concentration Genome-Wide Association Study: Functional Epistatic Interaction Between SLC38A7 and ALPPL2. Clin Pharmacol Ther. 2019 Jan 16.
• [12] In vitro and in vivo oxidative metabolism and glucuronidation of anastrozole. Br J Clin Pharmacol. 2010 Dec;70(6):854-69.
• [13] 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.
• [14] Aromatase inhibitors: cellular and molecular effects. J Steroid Biochem Mol Biol. 2005 May;95(1-5):83-9. doi: 10.1016/j.jsbmb.2005.04.010.
• [15] Aromatase inhibition: translation into a successful therapeutic approach. Clin Cancer Res. 2005 Apr 15;11(8):2809-21. doi: 10.1158/1078-0432.CCR-04-2187.
• [16] Assessment of Five Pesticides as Endocrine-Disrupting Chemicals: Effects on Estrogen Receptors and Aromatase. Int J Environ Res Public Health. 2022 Feb 10;19(4):1959. doi: 10.3390/ijerph19041959.
• [17] Inhibition of estrogen receptor reduces connexin 43 expression in breast cancers. Toxicol Appl Pharmacol. 2018 Jan 1;338:182-190. doi: 10.1016/j.taap.2017.11.020. Epub 2017 Nov 24.
• [18] Biomarker changes during neoadjuvant anastrozole, tamoxifen, or the combination: influence of hormonal status and HER-2 in breast cancer--a study from the IMPACT trialists. J Clin Oncol. 2005 Apr 10;23(11):2477-92. doi: 10.1200/JCO.2005.07.559. Epub 2005 Mar 14.
• [19] Knockouts model the 100 best-selling drugs--will they model the next 100 Nat Rev Drug Discov. 2003 Jan;2(1):38-51.
• [20] The genomic landscape of nasopharyngeal carcinoma.Nat Genet. 2014 Aug;46(8):866-71.
• [21] Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov. 2020 Mar 16;6:14.
• [22] Pharmacogenetics of tacrolimus and sirolimus in renal transplant patients: from retrospective analyses to prospective studies. Transplant Proc. 2007 Sep;39(7):2142-4.
• [23] 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.
• [24] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [25] Drug Interactions Flockhart Table