General Information of Drug Combination (ID: DCLPI78)

Drug Combination Name
Letrozole Mercaptopurine
Indication
Disease Entry Status REF
Glioma Investigative [1]
Component Drugs Letrozole   DMH07Y3 Mercaptopurine   DMTM2IK
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL
High-throughput Screening Result Testing Cell Line: SF-268
Zero Interaction Potency (ZIP) Score: 1.24
Bliss Independence Score: 9.1
Loewe Additivity Score: 1.75
LHighest Single Agent (HSA) Score: 2.2

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 [8]
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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 [9]
Aromatase (CYP19A1) DEQX145 CP19A_HUMAN Metabolism [10]
Cytochrome P450 2A6 (CYP2A6) DEJVYAZ CP2A6_HUMAN Metabolism [11]
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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 [12]
Cytochrome P450 3A4 (CYP3A4) OTQGYY83 CP3A4_HUMAN Increases Oxidation [13]
Cytochrome P450 2A6 (CYP2A6) OT52TWG3 CP2A6_HUMAN Increases Oxidation [13]
Adenylate kinase isoenzyme 1 (AK1) OT614AR3 KAD1_HUMAN Increases ADR [14]
Dickkopf-related protein 1 (DKK1) OTRDLUSP DKK1_HUMAN Increases Expression [15]
Follitropin subunit beta (FSHB) OTGLS283 FSHB_HUMAN Increases Expression [16]
Lutropin subunit beta (LHB) OT5GBOVJ LSHB_HUMAN Increases Expression [16]
Progesterone receptor (PGR) OT0FZ3QE PRGR_HUMAN Decreases Expression [17]
Leukemia inhibitory factor (LIF) OTO46S5S LIF_HUMAN Increases Expression [15]
Gap junction alpha-1 protein (GJA1) OTT94MKL CXA1_HUMAN Decreases Expression [18]
G1/S-specific cyclin-D1 (CCND1) OT8HPTKJ CCND1_HUMAN Decreases Expression [19]
G1/S-specific cyclin-D2 (CCND2) OTDULQF9 CCND2_HUMAN Decreases Expression [19]
Cyclin-dependent kinase inhibitor 1 (CDKN1A) OTQWHCZE CDN1A_HUMAN Increases Expression [20]
Leukemia inhibitory factor receptor (LIFR) OT36W9O5 LIFR_HUMAN Increases Expression [15]
Proliferation marker protein Ki-67 (MKI67) OTA8N1QI KI67_HUMAN Decreases Expression [17]
Small ribosomal subunit protein eS6 (RPS6) OTT4D1LN RS6_HUMAN Decreases Phosphorylation [19]
Lanosterol 14-alpha demethylase (CYP51A1) OTAYHG9C CP51A_HUMAN Decreases Activity [21]
Fibroblast growth factor 22 (FGF22) OTVIX6J0 FGF22_HUMAN Increases Expression [15]
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⏷ Show the Full List of 18 DOT(s)
Indication(s) of Mercaptopurine
Disease Entry ICD 11 Status REF
Acute lymphoblastic leukaemia 2A85 Approved [4]
Acute lymphocytic leukaemia 2B33.3 Approved [5]
Crohn disease DD70 Phase 4 [6]
Middle East Respiratory Syndrome (MERS) 1D64 Preclinical [7]
Severe acute respiratory syndrome (SARS) 1D65 Preclinical [7]
Mercaptopurine Interacts with 4 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
MERS-CoV papain-like proteinase (PL-PRO) TTYJOLE R1AB_CVEMC (854-2740) Inhibitor [7]
Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1) TTL7C8Q IMDH1_HUMAN Inhibitor [24]
SARS-CoV papain-like proteinase (PL-PRO) TTRGHB2 R1AB_CVHSA (819-2740) Inhibitor [7]
Amidophosphoribosyltransferase (PPAT) TTZFTY4 PUR1_HUMAN Breaker [25]
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Mercaptopurine Interacts with 9 DTP Molecule(s)
DTP Name DTP ID UniProt ID Mode of Action REF
Breast cancer resistance protein (ABCG2) DTI7UX6 ABCG2_HUMAN Substrate [26]
Multidrug resistance-associated protein 4 (ABCC4) DTCSGPB MRP4_HUMAN Substrate [27]
Multidrug resistance-associated protein 5 (ABCC5) DTYVM24 MRP5_HUMAN Substrate [28]
Organic anion transporter 3 (SLC22A8) DTVP67E S22A8_HUMAN Substrate [29]
Concentrative nucleoside transporter 2 (SLC28A2) DT82KPY S28A2_HUMAN Substrate [30]
Concentrative Na(+)-nucleoside cotransporter 3 (SLC28A3) DT4YL5R S28A3_HUMAN Substrate [31]
Equilibrative nucleoside transporter 1 (SLC29A1) DTXD1TQ S29A1_HUMAN Substrate [30]
Equilibrative nucleoside transporter 2 (SLC29A2) DTW78DQ S29A2_HUMAN Substrate [30]
Equilibrative nucleobase transporter 1 (SLC43A3) DTGBPR5 S43A3_HUMAN Substrate [32]
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⏷ Show the Full List of 9 DTP(s)
Mercaptopurine Interacts with 3 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
UDP-glucuronosyltransferase 1A1 (UGT1A1) DEYGVN4 UD11_HUMAN Metabolism [33]
Cytochrome P450 1A1 (CYP1A1) DE6OQ3W CP1A1_HUMAN Metabolism [33]
Thiopurine methyltransferase (TPMT) DEFQ8VO TPMT_HUMAN Metabolism [34]
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Mercaptopurine Interacts with 20 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Thiopurine S-methyltransferase (TPMT) OTFOX70W TPMT_HUMAN Affects Response To Substance [35]
Nuclear receptor subfamily 4 group A member 3 (NR4A3) OTPBE9R1 NR4A3_HUMAN Increases ADR [14]
Thiopurine S-methyltransferase (TPMT) OTFOX70W TPMT_HUMAN Decreases Metabolism [36]
Superoxide dismutase , mitochondrial (SOD2) OTIWXGZ9 SODM_HUMAN Increases Expression [37]
Inosine-5'-monophosphate dehydrogenase 2 (IMPDH2) OTPG0K7E IMDH2_HUMAN Increases Expression [37]
Glutathione peroxidase 2 (GPX2) OTXI2NTI GPX2_HUMAN Increases Expression [37]
Glutathione peroxidase 3 (GPX3) OT6PK94R GPX3_HUMAN Increases Expression [37]
Glutamate--cysteine ligase regulatory subunit (GCLM) OT6CP234 GSH0_HUMAN Increases Expression [37]
Glutathione synthetase (GSS) OTVSBEIW GSHB_HUMAN Increases Expression [37]
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) OTBPMIMW G3P_HUMAN Affects Localization [38]
Cellular tumor antigen p53 (TP53) OTIE1VH3 P53_HUMAN Affects Activity [39]
Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1) OT4Y9NQI MP2K1_HUMAN Decreases Phosphorylation [22]
Transcription factor p65 (RELA) OTUJP9CN TF65_HUMAN Affects Localization [22]
Bcl-2-like protein 1 (BCL2L1) OTRC5K9O B2CL1_HUMAN Decreases Expression [22]
Molybdenum cofactor sulfurase (MOCOS) OT0TL3Q5 MOCOS_HUMAN Decreases Oxidation [40]
HLA class II histocompatibility antigen, DQ alpha 1 chain (HLA-DQA1) OTC6GISG DQA1_HUMAN Affects Response To Substance [41]
Major vault protein (MVP) OTJGHJRB MVP_HUMAN Decreases Response To Substance [42]
HLA class II histocompatibility antigen, DRB1 beta chain (HLA-DRB1) OTRGGIFP DRB1_HUMAN Affects Response To Substance [41]
Glutathione S-transferase Mu 1 (GSTM1) OTSBF2MO GSTM1_HUMAN Affects Response To Substance [23]
Nucleotide triphosphate diphosphatase NUDT15 (NUDT15) OTX8SZOT NUD15_HUMAN Increases Response To Substance [43]
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⏷ Show the Full List of 20 DOT(s)

Test Results of This Drug Combination in Other Disease Systems

Indication DrugCom ID Cell Line Status REF
Adenocarcinoma DCCJJFI HCC-2998 Investigative [1]
Lung adenocarcinoma DCQKOND HOP-62 Investigative [1]
Plasma cell myeloma DCKSS77 RPMI-8226 Investigative [1]
Pleural epithelioid mesothelioma DCJH8G2 NCI-H226 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 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: 7226).
5 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
6 ClinicalTrials.gov (NCT00846703) The GD-2008 ALL Protocol for Childhood Acute Lymphoblastic Leukemia. U.S. National Institutes of Health.
7 Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus. Antiviral Res. 2015 Mar;115:9-16.
8 Aromatase inhibitors--theoretical concept and present experiences in the treatment of endometriosis. Zentralbl Gynakol. 2003 Jul-Aug;125(7-8):247-51.
9 Inhibition of drug metabolizing cytochrome P450s by the aromatase inhibitor drug letrozole and its major oxidative metabolite 4,4'-methanol-bisbenzonitrile in vitro. Cancer Chemother Pharmacol. 2009 Oct;64(5):867-75.
10 Double-blind, randomised, multicentre endocrine trial comparing two letrozole doses, in postmenopausal breast cancer patients. Eur J Cancer. 1999 Feb;35(2):208-13.
11 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.
12 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.
13 Deactivation of anti-cancer drug letrozole to a carbinol metabolite by polymorphic cytochrome P450 2A6 in human liver microsomes. Xenobiotica. 2009 Nov;39(11):795-802. doi: 10.3109/00498250903171395.
14 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.
15 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.
16 Aromatase inhibition, testosterone, and seizures. Epilepsy Behav. 2004 Apr;5(2):260-3. doi: 10.1016/j.yebeh.2003.12.001.
17 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.
18 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.
19 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.
20 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.
21 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.
22 CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest. 2003 Apr;111(8):1133-45. doi: 10.1172/JCI16432.
23 Pharmacogenetics of outcome in children with acute lymphoblastic leukemia. Blood. 2005 Jun 15;105(12):4752-8. doi: 10.1182/blood-2004-11-4544. Epub 2005 Feb 15.
24 Clinical pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol. 2008 Aug;64(8):753-67.
25 6-mercaptopurine (6-MP) induces p53-mediated apoptosis of neural progenitor cells in the developing fetal rodent brain. Neurotoxicol Teratol. 2009 Jul-Aug;31(4):198-202.
26 ABC transporters and their role in nucleoside and nucleotide drug resistance. Biochem Pharmacol. 2012 Apr 15;83(8):1073-83.
27 Polymorphisms in multidrug resistance-associated protein gene 4 is associated with outcome in childhood acute lymphoblastic leukemia. Blood. 2009 Aug 13;114(7):1383-6.
28 Overexpression of MRP4 (ABCC4) and MRP5 (ABCC5) confer resistance to the nucleoside analogs cytarabine and troxacitabine, but not gemcitabine. Springerplus. 2014 Dec 13;3:732.
29 Organic anion transporter 3 is involved in the brain-to-blood efflux transport of thiopurine nucleobase analogs. J Neurochem. 2004 Aug;90(4):931-41.
30 PharmGKB: A worldwide resource for pharmacogenomic information. Wiley Interdiscip Rev Syst Biol Med. 2018 Jul;10(4):e1417. (ID: PA2040)
31 Involvement of the concentrative nucleoside transporter 3 and equilibrative nucleoside transporter 2 in the resistance of T-lymphoblastic cell lines to thiopurines. Biochem Biophys Res Commun. 2006 Apr 28;343(1):208-15.
32 Characterization of 6-Mercaptopurine Transport by the SLC43A3-Encoded Nucleobase Transporter. Mol Pharmacol. 2019 Jun;95(6):584-596.
33 Pharmacogenomics in drug-metabolizing enzymes catalyzing anticancer drugs for personalized cancer chemotherapy. Curr Drug Metab. 2007 Aug;8(6):554-62.
34 The degree of myelosuppression during maintenance therapy of adolescents with B-lineage intermediate risk acute lymphoblastic leukemia predicts risk of relapse. Leukemia. 2010 Apr;24(4):715-20.
35 Low-dose azathioprine is effective and safe for maintenance of remission in patients with ulcerative colitis. J Gastroenterol. 2003;38(8):740-6. doi: 10.1007/s00535-003-1139-2.
36 Genetic polymorphisms of drug-metabolising enzymes and drug transporters in the chemotherapeutic treatment of cancer. Clin Pharmacokinet. 2006;45(3):253-85. doi: 10.2165/00003088-200645030-00003.
37 Petit E, Langouet S, Akhdar H, Nicolas-Nicolaz C, Guillouzo A, Morel F. Differential toxic effects of azathioprine, 6-mercaptopurine and 6-thioguanine on human hepatocytes. Toxicol In Vitro. 2008;22(3):632-642. [PMID: 18222062]
38 Glyceraldehyde 3-phosphate dehydrogenase depletion induces cell cycle arrest and resistance to antimetabolites in human carcinoma cell lines. J Pharmacol Exp Ther. 2009 Oct;331(1):77-86. doi: 10.1124/jpet.109.155671. Epub 2009 Jul 23.
39 Identification of environmental chemicals that activate p53 signaling after in vitro metabolic activation. Arch Toxicol. 2022 Jul;96(7):1975-1987. doi: 10.1007/s00204-022-03291-5. Epub 2022 Apr 18.
40 Thiopurine-induced toxicity is associated with dysfunction variant of the human molybdenum cofactor sulfurase gene (xanthinuria type II). Toxicol Appl Pharmacol. 2018 Aug 15;353:102-108. doi: 10.1016/j.taap.2018.06.015. Epub 2018 Jun 20.
41 HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants. Nat Genet. 2014 Oct;46(10):1131-4. doi: 10.1038/ng.3093. Epub 2014 Sep 14.
42 Sensitization of ABCG2-overexpressing cells to conventional chemotherapeutic agent by sunitinib was associated with inhibiting the function of ABCG2. Cancer Lett. 2009 Jun 28;279(1):74-83. doi: 10.1016/j.canlet.2009.01.027. Epub 2009 Feb 18.
43 A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet. 2014 Sep;46(9):1017-20. doi: 10.1038/ng.3060. Epub 2014 Aug 10.