General Information of Drug Combination (ID: DC565RC)

Drug Combination Name
Exemestane Letrozole
Indication
Disease Entry Status REF
Male Breast Cancer Phase 1 [1]
Component Drugs Exemestane   DM9HPW3 Letrozole   DMH07Y3
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
Indication(s) of Exemestane
Disease Entry ICD 11 Status REF
Hormonally-responsive breast cancer 2C60-2C65 Approved [2]
Male breast carcinoma N.A. Investigative [3]
Exemestane Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Aromatase (CYP19A1) TTSZLWK CP19A_HUMAN Inhibitor [6]
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Exemestane Interacts with 1 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) DE4LYSA CP3A4_HUMAN Metabolism [7]
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Exemestane Interacts with 30 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Adenylate kinase isoenzyme 1 (AK1) OT614AR3 KAD1_HUMAN Increases ADR [8]
Trefoil factor 1 (TFF1) OTCYQH4F TFF1_HUMAN Increases Expression [9]
Progesterone receptor (PGR) OT0FZ3QE PRGR_HUMAN Increases Expression [9]
Myb-related protein B (MYBL2) OTZ3JX8Q MYBB_HUMAN Increases Expression [10]
Androgen receptor (AR) OTUBKAZZ ANDR_HUMAN Affects Localization [11]
Aromatase (CYP19A1) OTZ6XF74 CP19A_HUMAN Decreases Activity [12]
Amphiregulin (AREG) OTJFOR67 AREG_HUMAN Increases Expression [9]
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 (PLCG2) OTGVC9MY PLCG2_HUMAN Increases Expression [10]
Homeobox protein Hox-D11 (HOXD11) OT9XGA4G HXD11_HUMAN Increases Expression [10]
Pituitary adenylate cyclase-activating polypeptide type I receptor (ADCYAP1R1) OTNBHULA PACR_HUMAN Increases Expression [10]
Proliferation marker protein Ki-67 (MKI67) OTA8N1QI KI67_HUMAN Decreases Expression [13]
Kallikrein-7 (KLK7) OTIWGMO2 KLK7_HUMAN Increases Expression [10]
Disabled homolog 2 (DAB2) OTRMQTMZ DAB2_HUMAN Increases Expression [10]
CD83 antigen (CD83) OT1V4WQF CD83_HUMAN Increases Expression [10]
Unconventional myosin-IXb (MYO9B) OTQ94R5K MYO9B_HUMAN Increases Expression [10]
RRP12-like protein (RRP12) OTQQAEH4 RRP12_HUMAN Increases Expression [10]
Dynein axonemal assembly factor 9 (DNAAF9) OTTKWWQU DAAF9_HUMAN Increases Expression [10]
E3 ubiquitin-protein ligase RNF123 (RNF123) OTL59S8J RN123_HUMAN Increases Expression [10]
Osteopetrosis-associated transmembrane protein 1 (OSTM1) OTKNJDH7 OSTM1_HUMAN Increases Expression [10]
Glypican-2 (GPC2) OT3WSQE1 GPC2_HUMAN Increases Expression [10]
Tumor necrosis factor receptor superfamily member 14 (TNFRSF14) OTB82PFO TNR14_HUMAN Increases Expression [10]
Integrator complex subunit 4 (INTS4) OT5JQ913 INT4_HUMAN Increases Expression [10]
Inositol polyphosphate 5-phosphatase K (INPP5K) OTQFLQKA INP5K_HUMAN Increases Expression [10]
ATP-binding cassette sub-family G member 4 (ABCG4) OT2XJIOG ABCG4_HUMAN Increases Expression [10]
TRIO and F-actin-binding protein (TRIOBP) OTGB5WHC TARA_HUMAN Increases Expression [10]
TBC1 domain family member 17 (TBC1D17) OT75ZWLB TBC17_HUMAN Increases Expression [10]
Kinesin-like protein KIF13B (KIF13B) OTAFS1YV KI13B_HUMAN Increases Expression [10]
Transcription factor COE1 (EBF1) OTZ61YYH COE1_HUMAN Increases Expression [10]
Meteorin (METRN) OTI2645G METRN_HUMAN Increases Expression [10]
Solute carrier family 13 member 4 (SLC13A4) OTP3N8N3 S13A4_HUMAN Increases Expression [10]
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⏷ Show the Full List of 30 DOT(s)
Indication(s) of Letrozole
Disease Entry ICD 11 Status REF
Estrogen-receptor positive breast cancer N.A. Approved [4]
Hormonally-responsive breast cancer 2C60-2C65 Approved [5]
Letrozole Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Aromatase (CYP19A1) TTSZLWK CP19A_HUMAN Inhibitor [6]
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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 [14]
Aromatase (CYP19A1) DEQX145 CP19A_HUMAN Metabolism [15]
Cytochrome P450 2A6 (CYP2A6) DEJVYAZ CP2A6_HUMAN Metabolism [16]
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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 [17]
Cytochrome P450 2A6 (CYP2A6) OT52TWG3 CP2A6_HUMAN Increases Oxidation [17]
Adenylate kinase isoenzyme 1 (AK1) OT614AR3 KAD1_HUMAN Increases ADR [8]
Dickkopf-related protein 1 (DKK1) OTRDLUSP DKK1_HUMAN Increases Expression [18]
Follitropin subunit beta (FSHB) OTGLS283 FSHB_HUMAN Increases Expression [19]
Lutropin subunit beta (LHB) OT5GBOVJ LSHB_HUMAN Increases Expression [19]
Progesterone receptor (PGR) OT0FZ3QE PRGR_HUMAN Decreases Expression [13]
Leukemia inhibitory factor (LIF) OTO46S5S LIF_HUMAN Increases Expression [18]
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 [18]
Proliferation marker protein Ki-67 (MKI67) OTA8N1QI KI67_HUMAN Decreases Expression [13]
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 [18]
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⏷ Show the Full List of 18 DOT(s)

Test Results of This Drug Combination in Other Disease Systems

Indication DrugCom ID Cell Line Status REF
Breast Cancer DCSL7NG N. A. Phase 3 [24]
Breast Cancer DC93Z3D N. A. Phase 3 [25]
Estrogen Receptor Negative DCUQK86 N. A. Phase 2 [26]
Breast Cancer DCZHHUA N. A. Phase 2 [27]
Breast Cancer DCL9I4L N. A. Phase 1 [28]
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References

1 ClinicalTrials.gov (NCT01153672) Vorinostat in Treating Patients With Stage IV Breast Cancer Receiving Aromatase Inhibitor Therapy
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: 7073).
3 Exemestane FDA Label
4 Letrozole FDA Label
5 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).
6 Aromatase inhibitors--theoretical concept and present experiences in the treatment of endometriosis. Zentralbl Gynakol. 2003 Jul-Aug;125(7-8):247-51.
7 In vitro metabolism of exemestane by hepatic cytochrome P450s: impact of nonsynonymous polymorphisms on formation of the active metabolite 17beta-dihydroexemestane. Pharmacol Res Perspect. 2017 Apr 27;5(3):e00314.
8 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.
9 Characterization of the weak estrogen receptor alpha agonistic activity of exemestane. Breast Cancer Res Treat. 2009 Aug;116(3):461-70. doi: 10.1007/s10549-008-0151-x. Epub 2008 Aug 3.
10 Effects of aromatase inhibitors on human osteoblast and osteoblast-like cells: a possible androgenic bone protective effects induced by exemestane. Bone. 2007 Apr;40(4):876-87. doi: 10.1016/j.bone.2006.11.029. Epub 2006 Dec 28.
11 Identifying environmental chemicals as agonists of the androgen receptor by using a quantitative high-throughput screening platform. Toxicology. 2017 Jun 15;385:48-58. doi: 10.1016/j.tox.2017.05.001. Epub 2017 May 4.
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 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.
14 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.
15 Double-blind, randomised, multicentre endocrine trial comparing two letrozole doses, in postmenopausal breast cancer patients. Eur J Cancer. 1999 Feb;35(2):208-13.
16 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.
17 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.
18 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.
19 Aromatase inhibition, testosterone, and seizures. Epilepsy Behav. 2004 Apr;5(2):260-3. doi: 10.1016/j.yebeh.2003.12.001.
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 ClinicalTrials.gov (NCT02995772) Neoadjuvant Hormonal Therapy Compared to Neoadjuvant Chemotherapy in Stage IIIB/C and IV Breast Cancer Patients
25 ClinicalTrials.gov (NCT00893061) Letrozole, Anastrozole, Exemestane, or Tamoxifen Citrate in Treating Postmenopausal Women With Breast Cancer
26 ClinicalTrials.gov (NCT02648477) Pembrolizumab and Doxorubicin Hydrochloride or Anti-Estrogen Therapy in Treating Patients With Triple-Negative or Hormone Receptor-Positive Metastatic Breast Cancer
27 ClinicalTrials.gov (NCT00573755) Sorafenib and Letrozole, Anastrozole, or Exemestane in Treating Postmenopausal Women With Estrogen Receptor-Positive and/or Progesterone Receptor-Positive Metastatic Breast Cancer
28 ClinicalTrials.gov (NCT00719966) Effect of Aromatase Inhibitor Therapy on Blood Vessel Function in Postmenopausal Women With Breast Cancer