Last update 01 Nov 2024

ERβ x STS x ERα

Last update 01 Nov 2024

Basic Info

Related Targets

ERβSTSERα

Drugs associated with ERβ x STS x ERα

HLX-801

Target

ERα x ERβ x STS

Mechanism

ERα antagonists [+2]

Active Org.

Helix Therapeutics, Inc.

Originator Org.

SRI International

Active Indication

Breast Cancer

Inactive Indication-

Drug Highest PhasePhase 2

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with ERβ x STS x ERα

100 Translational Medicine associated with ERβ x STS x ERα

0 Patents (Medical) associated with ERβ x STS x ERα

Literatures (Medical) associated with ERβ x STS x ERα

09 Aug 2024·Combinatorial Chemistry & High Throughput Screening

Investigation of Fructus Ligustri Lucidi for Premature Ovarian Insufficiency based on a Network Pharmacology and Experiment Verifications

Article

Author: Luo, Xi ; Cai, Wang-Yu

Introduction:Premature ovarian insufficiency [POI] is a disease characterized by a premature decline in ovarian function before the age of 40. In China, Ligustrum lucidum [FLL] has long been used to improve ovarian function and treat POI.Methods:This study aims to verify the effect of FLL on POI through network pharmacology, molecular docking, and in-vitro cell experiments.Results:A total of 13 active substances were screened in FLL, including including quercetin, taxifolin, luteolin, kaempferol, and beta-sitosterol. Then, network analysis found that FLL may exert effects on POI through 10 targets, including AR, ESR1, ESR2, KDR, CYP19A1, CLPP, GC, MMP3, PPARG, and STS. According to GO and KEGG enrichment analysis, FLL is associated with mechanisms related to estrogen, including steroid hormone biosynthesis, ovarian steroidogenesis, and the estrogen signaling pathway. Molecular docking confirms the interaction between the active ingredients of FLL and CYP19A1, which encodes aromatase. CCK8 experiment confirmed that quercetin and taxifolin can enhance the proliferation of KGN granulosa cells, while quercetin, taxifolin, and kaempferol can inhibit the apoptosis of KGN granulosa cells. ELISA experiments have confirmed that quercetin, taxifolin, luteolin, and kaempferol can increase the synthesis of estradiol in KGN granulosa cells. WB confirms that quercetin can increase the expression level of CYP19A1 in KGN cells.Conclusion:FLL can improve the proliferation, apoptosis, and synthesis of estradiol in ovarian granulosa cells, and has the potential to treat POI.

01 Mar 2024·Bioorganic & Medicinal Chemistry

Synthesis, biological evaluation, and stability studies of raloxifene mono- and bis-sulfamates as dual-targeting agents

Article

Author: El-Gamal, Mohammed I ; Potter, Barry V L ; El-Gamal, Randa ; Foster, Paul A ; Dohle, Wolfgang ; Al-Tel, Taleb H ; Anbar, Hanan S ; Leblond, Bertrand ; Zaraei, Seyed-Omar

All three possible sulfamate derivatives of the selective estrogen receptor modulator Raloxifene (bis-sulfamate 7 and two mono-sulfamates 8-9) were synthesized and evaluated as inhibitors of the clinical drug target steroid sulfatase (STS), both in cell-free and in cell-based assays, and also as estrogen receptor (ER) modulators. Bis-sulfamate 7 was the most potent STS inhibitor with an IC₅₀ of 12.2 nM in a whole JEG3 cell-based assay, with the two mono-sulfamates significantly weaker. The estrogen receptor-modulating activities of 7-9 showed generally lower affinities compared to Raloxifene HCl, diethylstilbestrol and other known ligands, with mono-sulfamate 8 being the best ligand (Ki of 1.5 nM) for ERα binding, although 7 had a Ki of 13 nM and both showed desirable antagonist activity. The antiproliferative activities of the sulfamate derivatives against the T-47D breast cancer cell line showed 7 as most potent (GI₅₀ = 7.12 µM), comparable to that of Raloxifene. Compound 7 also showed good antiproliferative potency in the NCI-60 cell line panel with a GI₅₀ of 1.34 µM against MDA-MB-231 breast cancer cells. Stability testing of 7-9 showed that bis-sulfamate 7 hydrolyzed by desulfamoylation at a surprisingly rapid rate, initially leading selectively to 8 and finally to Raloxifene 3 without formation of 9. The mechanisms of these hydrolysis reactions could be extensively rationalized. Conversion of Raloxifene (3) into its bis-sulfamate (7) thus produced a promising drug lead with nanomolar dual activity as an STS inhibitor and ERα antagonist, as a potential candidate for treatment of estrogen-dependent breast cancer.

01 Jan 2021·Bulletin of Experimental Biology and MedicineQ4 · MEDICINE

Features of the Copy Number Variation of Certain Genes in Tumor Cells in Patients with Serous Ovarian Adenocarcinoma

Q4 · MEDICINE

Article

Author: Porkhanova, N V ; Tsandekova, M R ; Kutilin, D S

We analyzed the peculiarities of the copy number variation of genes that regulate apoptosis, DNA repair, cell proliferation, metabolism, and estrogen reception in tumor and normal cells of high-grade and low-grade serous adenocarcinoma of the ovaries. Using real-time qPCR method, the relative copy number of 34 genes (BAX, BCL2, TP53, MDM2, CASP9, CASP3, CASP7, CASP8, PRKCI, SOX2, OCT4, PIK3, PTEN, C-MYC, SOX18, AKT1, NOTCH1, BRCA1, BRCA2, EXO1, SCNN1A, KRAS, EGFR, BRAF, CYP1A1, CYP1A2, CYP1B1, CYP19A, ESR1, ESR2, GPER, STS, SULT1A, and SULT1E1) was determined in normal and tumor cells of the ovaries extracted by contactless capture laser microsection from FFPE-blocks of 200 patients. The most typical molecular markers of ovarian serous adenocarcinoma cells were identified: copy number of PIK3CA, BCL2, BAX, CASP3, and CASP8 genes. Based on the differences in the gene copy number variation, two molecular subtypes of serous adenocarcinoma were identified, corresponding to two histological subtypes: high-grade (MDM2, SOX2, ESR1, CYP1B1, SULT1E1, TP53, BRCA2) and low-grade (PIK3CA, PTEN, BCL2, BAX, and CASP3). Each of these subtypes was also characterized by molecular heterogeneity and can be subdivided into several subgroups: 3 subgroups for high-grade and 4 subgroups for low-grade serous adenocarcinoma. These findings extend our understanding of the molecular mechanisms of carcinogenesis in the ovarian tissue, confirm molecular difference between the two histological subtypes of serous adenocarcinoma probably underlying their different clinical course.

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