General Information of Drug Combination (ID: DCTTCWH)

Drug Combination Name
Vismodegib Letrozole
Indication
Disease Entry Status REF
High grade ovarian serous adenocarcinoma Investigative [1]
Component Drugs Vismodegib   DM5IXKQ Letrozole   DMH07Y3
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL
High-throughput Screening Result Testing Cell Line: OVCAR-4
Zero Interaction Potency (ZIP) Score: 4.16
Bliss Independence Score: 1.48
Loewe Additivity Score: 0.45
LHighest Single Agent (HSA) Score: 0.5

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
Indication(s) of Vismodegib
Disease Entry ICD 11 Status REF
Basal cell carcinoma 2C32 Approved [2]
Primitive neuroectodermal tumour medulloblastoma 2A00.11 Phase 2 [3]
Vismodegib Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Smoothened homolog (SMO) TT8J1S3 SMO_HUMAN Modulator [6]
------------------------------------------------------------------------------------
Vismodegib Interacts with 2 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) DE4LYSA CP3A4_HUMAN Metabolism [7]
Cytochrome P450 2C9 (CYP2C9) DE5IED8 CP2C9_HUMAN Metabolism [7]
------------------------------------------------------------------------------------
Vismodegib Interacts with 13 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Tumor necrosis factor receptor superfamily member 10A (TNFRSF10A) OTBPCU2O TR10A_HUMAN Increases Expression [8]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B) OTA1CPBV TR10B_HUMAN Increases Expression [8]
Zinc finger protein GLI1 (GLI1) OT1BTAJO GLI1_HUMAN Decreases Expression [8]
Zinc finger protein GLI2 (GLI2) OTIRV97L GLI2_HUMAN Decreases Expression [8]
Apoptosis regulator Bcl-2 (BCL2) OT9DVHC0 BCL2_HUMAN Decreases Expression [8]
Platelet-derived growth factor receptor alpha (PDGFRA) OTDJXUCN PGFRA_HUMAN Decreases Expression [8]
Tumor necrosis factor receptor superfamily member 6 (FAS) OTP9XG86 TNR6_HUMAN Increases Expression [8]
Caspase-3 (CASP3) OTIJRBE7 CASP3_HUMAN Increases Cleavage [8]
Protein patched homolog 1 (PTCH1) OTMG07H5 PTC1_HUMAN Decreases Expression [8]
Protein smoothened (SMO) OTXXE208 SMO_HUMAN Decreases Expression [8]
Protein patched homolog 2 (PTCH2) OTOQ0K9V PTC2_HUMAN Decreases Expression [8]
Suppressor of fused homolog (SUFU) OT0IRYG1 SUFU_HUMAN Decreases Response To Substance [9]
N-myc proto-oncogene protein (MYCN) OTWD33K1 MYCN_HUMAN Decreases Response To Substance [9]
------------------------------------------------------------------------------------
⏷ Show the Full List of 13 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 [10]
------------------------------------------------------------------------------------
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]
------------------------------------------------------------------------------------
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]
------------------------------------------------------------------------------------
⏷ 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
Carcinoma DCBRM4Z MCF7 Investigative [24]
Invasive ductal carcinoma DCDJ3U4 BT-549 Investigative [24]
Invasive ductal carcinoma DCNDIJ8 HS 578T Investigative [24]
Adenocarcinoma DCW4KXY NCIH23 Investigative [1]
Adenocarcinoma DCPR1JI SW-620 Investigative [1]
Adenocarcinoma DCBNUML HT29 Investigative [1]
Adult acute myeloid leukemia DCCNPM5 HL-60(TB) Investigative [1]
Adult T acute lymphoblastic leukemia DCQKII7 MOLT-4 Investigative [1]
Amelanotic melanoma DCB1BTO M14 Investigative [1]
Amelanotic melanoma DCJSSM6 MDA-MB-435 Investigative [1]
Astrocytoma DCAWV0D SNB-19 Investigative [1]
Clear cell renal cell carcinoma DCOQI9I TK-10 Investigative [1]
Cutaneous melanoma DCOCUPH SK-MEL-28 Investigative [1]
Cutaneous melanoma DCTCPTX SK-MEL-5 Investigative [1]
Glioma DC5PXRA SF-268 Investigative [1]
High grade ovarian serous adenocarcinoma DC9H3HA OVCAR-8 Investigative [1]
Malignant melanoma DC7HWT4 LOX IMVI Investigative [1]
Melanoma DCLIOJX UACC-257 Investigative [1]
Melanoma DC95AU0 MALME-3M Investigative [1]
Minimally invasive lung adenocarcinoma DC62KIR NCI-H322M Investigative [1]
Plasma cell myeloma DC9JE2Y RPMI-8226 Investigative [1]
Pleural epithelioid mesothelioma DC4V1OJ NCI-H226 Investigative [1]
Renal cell carcinoma DCGZNA5 SN12C Investigative [1]
------------------------------------------------------------------------------------
⏷ Show the Full List of 23 DrugCom(s)

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: 6975).
3 A phase II, multicenter, open-label, 3-cohort trial evaluating the efficacy and safety of vismodegib in operable basal cell carcinoma. J Am Acad Dermatol. 2015 Jul;73(1):99-105.e1.
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 Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
7 The dawn of hedgehog inhibitors: Vismodegib. J Pharmacol Pharmacother. 2013 Jan;4(1):4-7.
8 Hedgehog signaling antagonist GDC-0449 (Vismodegib) inhibits pancreatic cancer stem cell characteristics: molecular mechanisms. PLoS One. 2011;6(11):e27306. doi: 10.1371/journal.pone.0027306. Epub 2011 Nov 8.
9 Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition. Nat Med. 2014 Jul;20(7):732-40. doi: 10.1038/nm.3613. Epub 2014 Jun 29.
10 Aromatase inhibitors--theoretical concept and present experiences in the treatment of endometriosis. Zentralbl Gynakol. 2003 Jul-Aug;125(7-8):247-51.
11 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.
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.
15 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.
16 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.
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.
18 Aromatase inhibition, testosterone, and seizures. Epilepsy Behav. 2004 Apr;5(2):260-3. doi: 10.1016/j.yebeh.2003.12.001.
19 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.
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 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.