General Information of Drug Combination (ID: DC4MYEK)

Drug Combination Name
Letrozole Sirolimus
Indication
Disease Entry Status REF
Adult T acute lymphoblastic leukemia Investigative [1]
Component Drugs Letrozole   DMH07Y3 Sirolimus   DMGW1ID
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL
High-throughput Screening Result Testing Cell Line: MOLT-4
Zero Interaction Potency (ZIP) Score: 3.65
Bliss Independence Score: 5.66
Loewe Additivity Score: 4.85
LHighest Single Agent (HSA) Score: 8.73

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
Indication(s) of Letrozole
Disease Entry ICD 11 Status REF
Estrogen-receptor positive breast cancer N.A. Approved [2]
Hormonally-responsive breast cancer 2C60-2C65 Approved [3]
Letrozole Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Aromatase (CYP19A1) TTSZLWK CP19A_HUMAN Inhibitor [10]
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Letrozole 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]
Aromatase (CYP19A1) DEQX145 CP19A_HUMAN Metabolism [12]
Cytochrome P450 2A6 (CYP2A6) DEJVYAZ CP2A6_HUMAN Metabolism [13]
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Letrozole Interacts with 18 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Aromatase (CYP19A1) OTZ6XF74 CP19A_HUMAN Decreases Activity [14]
Cytochrome P450 3A4 (CYP3A4) OTQGYY83 CP3A4_HUMAN Increases Oxidation [15]
Cytochrome P450 2A6 (CYP2A6) OT52TWG3 CP2A6_HUMAN Increases Oxidation [15]
Adenylate kinase isoenzyme 1 (AK1) OT614AR3 KAD1_HUMAN Increases ADR [16]
Dickkopf-related protein 1 (DKK1) OTRDLUSP DKK1_HUMAN Increases Expression [17]
Follitropin subunit beta (FSHB) OTGLS283 FSHB_HUMAN Increases Expression [18]
Lutropin subunit beta (LHB) OT5GBOVJ LSHB_HUMAN Increases Expression [18]
Progesterone receptor (PGR) OT0FZ3QE PRGR_HUMAN Decreases Expression [19]
Leukemia inhibitory factor (LIF) OTO46S5S LIF_HUMAN Increases Expression [17]
Gap junction alpha-1 protein (GJA1) OTT94MKL CXA1_HUMAN Decreases Expression [20]
G1/S-specific cyclin-D1 (CCND1) OT8HPTKJ CCND1_HUMAN Decreases Expression [21]
G1/S-specific cyclin-D2 (CCND2) OTDULQF9 CCND2_HUMAN Decreases Expression [21]
Cyclin-dependent kinase inhibitor 1 (CDKN1A) OTQWHCZE CDN1A_HUMAN Increases Expression [22]
Leukemia inhibitory factor receptor (LIFR) OT36W9O5 LIFR_HUMAN Increases Expression [17]
Proliferation marker protein Ki-67 (MKI67) OTA8N1QI KI67_HUMAN Decreases Expression [19]
Small ribosomal subunit protein eS6 (RPS6) OTT4D1LN RS6_HUMAN Decreases Phosphorylation [21]
Lanosterol 14-alpha demethylase (CYP51A1) OTAYHG9C CP51A_HUMAN Decreases Activity [23]
Fibroblast growth factor 22 (FGF22) OTVIX6J0 FGF22_HUMAN Increases Expression [17]
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⏷ Show the Full List of 18 DOT(s)
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 [24]
PI3K/AKT/mTOR pathway (PAm pathway) TTGQUFK NOUNIPROTAC Inhibitor [25]
HUMAN mammalian target of rapamycin (mTOR) TT7HQAF MTOR_HUMAN Inhibitor [26]
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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 [27]
Organic anion transporting polypeptide 1B1 (SLCO1B1) DT3D8F0 SO1B1_HUMAN Substrate [28]
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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 [29]
Cytochrome P450 3A5 (CYP3A5) DEIBDNY CP3A5_HUMAN Metabolism [30]
Cytochrome P450 3A7 (CYP3A7) DERD86B CP3A7_HUMAN Metabolism [30]
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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]
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Test Results of This Drug Combination in Other Disease Systems

Indication DrugCom ID Cell Line Status REF
High grade ovarian serous adenocarcinoma DCNBP7W NCI\\/ADR-RES Investigative [1]
Plasma cell myeloma DC4DE81 RPMI-8226 Investigative [1]
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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 Letrozole FDA Label
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: 5209).
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.
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12 Double-blind, randomised, multicentre endocrine trial comparing two letrozole doses, in postmenopausal breast cancer patients. Eur J Cancer. 1999 Feb;35(2):208-13.
13 Letrozole concentration is associated with CYP2A6 variation but not with arthralgia in patients with breast cancer. Breast Cancer Res Treat. 2018 Nov;172(2):371-379.
14 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.
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17 Clomiphene citrate versus letrozole: molecular analysis of the endometrium in women with polycystic ovary syndrome. Fertil Steril. 2011 Oct;96(4):1051-6. doi: 10.1016/j.fertnstert.2011.07.1092.
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20 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.
21 Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer. Clin Cancer Res. 2005 Jul 15;11(14):5319-28. doi: 10.1158/1078-0432.CCR-04-2402.
22 Synergistic activity of letrozole and sorafenib on breast cancer cells. Breast Cancer Res Treat. 2010 Nov;124(1):79-88. doi: 10.1007/s10549-009-0714-5. Epub 2010 Jan 7.
23 Comparison of lanosterol-14 alpha-demethylase (CYP51) of human and Candida albicans for inhibition by different antifungal azoles. Toxicology. 2006 Nov 10;228(1):24-32. doi: 10.1016/j.tox.2006.08.007. Epub 2006 Aug 12.
24 Knockouts model the 100 best-selling drugs--will they model the next 100 Nat Rev Drug Discov. 2003 Jan;2(1):38-51.
25 The genomic landscape of nasopharyngeal carcinoma.Nat Genet. 2014 Aug;46(8):866-71.
26 Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov. 2020 Mar 16;6:14.
27 Pharmacogenetics of tacrolimus and sirolimus in renal transplant patients: from retrospective analyses to prospective studies. Transplant Proc. 2007 Sep;39(7):2142-4.
28 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.
29 Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
30 Drug Interactions Flockhart Table