Search Results (227)

Hormone-dependent breast cancer, particularly in its treatment-resistant forms, remains a significant therapeutic challenge. In this study, we applied a fully computational strategy to design steroid-based compounds capable of simultaneously targeting three key receptors involved in disease progression: progesterone receptor (PR), estrogen receptor alpha (ER-α), and HER2. Using a robust 3D-QSAR model (R² = 0.86; Q²_LOO = 0.86) built from 52 steroidal structures, we identified molecular features associated with high anticancer potential, specifically increased polarizability and reduced electronegativity. From a virtual library of 271 DFT-optimized analogs, 31 compounds were selected based on predicted potency (pIC₅₀ > 7.0) and screened via molecular docking against PR (PDB 2W8Y), HER2 (PDB 7JXH), and ER-α (PDB 6VJD). Seven candidates showed strong binding affinities (ΔG ≤ −9 kcal/mol for at least two targets), with Estero-255 emerging as the most promising. This compound demonstrated excellent conformational stability, a robust hydrogen-bonding network, and consistent multitarget engagement. Molecular dynamics simulations over 100 nanoseconds confirmed the structural integrity of the top ligands, with low RMSD values, compact radii of gyration, and stable binding energy profiles. Key interactions included hydrophobic contacts, π–π stacking, halogen–π interactions, and classical hydrogen bonds with conserved residues across all three targets. These findings highlight Estero-255, alongside Estero-261 and Estero-264, as strong multitarget candidates for further development. By potentially disrupting the PI3K/AKT/mTOR signaling pathway, these compounds offer a promising strategy for overcoming resistance in hormone-driven breast cancer. Experimental validation, including cytotoxicity assays and ADME/Tox profiling, is recommended to confirm their therapeutic potential. Full article

Estrogen receptor alpha (ERα) plays a vital role in the development and progression of breast cancer by regulating the expression of genes associated with cell proliferation in breast tissue. ERα inhibition is a key strategy in the prevention and treatment of breast cancer. Previous research modified chalcone compounds into pyrazoline benzenesulfonamide derivatives (Modifina) which show activity as an ERα inhibitor. This study aimed to design novel pyrazoline benzenesulfonamide derivatives (PBDs) as ERα antagonists using in silico approaches. Structure-based and ligand-based drug design approaches were used to create drug target molecules. A total of forty-five target molecules were initially designed and screened for drug likeness (Lipinski’s rule of five), cytotoxicity, pharmacokinetics and toxicity using a web-based prediction tools. Promising candidates were subjected to molecular docking using AutoDock 4.2.6 to evaluate their binding interaction with ERα, followed by molecular dynamics simulations using AMBER20 to assess complex stability. A pharmacophore model was also generated using LigandScout 4.4.3 Advanced. The molecular docking results identified PBD-17 and PBD-20 as the most promising compounds, with binding free energies (ΔG) of −11.21 kcal/mol and −11.15 kcal/mol, respectively. Both formed hydrogen bonds with key ERα residues ARG394, GLU353, and LEU387. MM-PBSA further supported these findings, with binding energies of −58.23 kJ/mol for PDB-17 and −139.46 kJ/mol for PDB-20, compared to −145.31 kJ/mol, for the reference compound, 4-OHT. Although slightly less favorable than 4-OHT, PBD-20 demonstrated a more stable interaction with ERα than PBD-17. Furthermore, pharmacophore screening showed that both PBD-17 and PBD-20 aligned well with the generated model, each achieving a match score of 45.20. These findings suggest that PBD-17 and PBD-20 are promising lead compounds for the development of a potent ERα inhibitor in breast cancer therapy. Full article

Background: Targeted therapies, such as endocrine agents, have significantly improved outcomes for patients with estrogen receptor alpha-positive (ERα+) breast cancer. Unfortunately, for patients with triple-negative breast cancer (TNBC), which lack expression of ERα and HER2, there remains a dearth of targeted adjuvant agents. We discovered that estrogen receptor beta (ERβ) is expressed in approximately 20% of TNBC cases, and its activation has been shown to inhibit proliferation, invasion, and migration in preclinical models. However, it remains unclear whether ERβ-targeted therapies maintain efficacy following the development of chemoresistance. Methods: To address this question, we generated ERβ+ TNBC cell line models with acquired resistance to paclitaxel or doxorubicin. We then assessed their response to ERβ-targeted therapies and analyzed transcriptomic changes associated with chemoresistance and ERβ ligand treatment. Results: Chemotherapy-resistant ERβ+ TNBC cells retained sensitivity to ERβ-targeted therapies and, in some cases, exhibited enhanced responsiveness. ERβ expression did not compromise chemotherapy efficacy in treatment-naïve cells. Chemotherapy-resistant cells had a vastly altered transcriptome and surprisingly, a heavily reduced ERβ transcriptome, compared to sensitive cells despite the maintenance of ERβ-driven anti-neoplastic activity. Conclusions: These findings suggest that ERβ remains a relevant drug target in chemotherapy-refractory disease and has aided in the refinement of a minimal ERβ transcriptomic signature associated with response to ERβ-targeting agents, further informing the primary mechanisms through which ERβ elicits its tumor suppressive effects. Full article

Transcription factors (TFs) play central roles in gene regulation and disease progression but have long been considered undruggable due to the absence of well-defined binding pockets and their reliance on protein–protein or protein–DNA interactions. Proteolysis-targeting chimeras (PROTACs) offer a novel strategy to overcome these limitations by inducing selective degradation of TFs via the ubiquitin–proteasome system. This review highlights recent advances in TF-targeting PROTACs, focusing on key oncogenic TFs such as androgen receptor (AR), estrogen receptor alpha (ERα), BRD4, c-Myc, and STAT family members. Strategies for ligand design—including small molecules, peptides, and nucleic acid-based elements—are discussed alongside the use of various E3 ligases such as VHL, CRBN, and IAP. Several clinically advanced PROTACs, including ARV-110 and ARV-471, demonstrate the therapeutic potential of this technology. Despite challenges in pharmacokinetics and E3 ligase selection, emerging data suggest that PROTACs can successfully target TFs, paving the way for new treatment strategies across oncology and other disease areas. Full article

We previously reported that the level of EGFR expression is directly associated with the survival rate of estrogen receptor-positive (ER+) breast cancer patients. Here, we investigated how ER activation by 17β-estradiol (E2), the most potent form of estrogen, affects the expression or activity of EGFR or EGFR-related genes in ER+ breast cancer cells. As expected, E2 enhanced cell proliferation, the induction of S phase, and tumor growth in ER+ breast cancer models. E2 also increased the expression of secretory proteins, including amphiregulin (AREG), angiogenin, artemin, and CXCL16. We focused on AREG, which is a ligand of the epidermal growth factor receptor (EGFR). The levels of AREG expression were positively correlated with ESR1 expression. Our results also showed higher AREG mRNA expression levels in ER+ breast cancer cells than in ER- breast cancer cells. We treated ER+ breast cancer cells with lapatinib to inhibit the AREG/EGFR signaling pathway and then completely inhibited E2-induced cell proliferation and S-phase induction. Similar to the lapatinib treatment, cell proliferation, S-phase induction, cell migration, and tumor growth were suppressed by AREG knockdown. Taken together, we demonstrated that the induction of AREG by E2 contributes to EGFR activation, which then affects cell proliferation and tumor growth. Therefore, we suggest that AREG acts as an intermediary between EGFR and ER and targeting both ERs and EGFRs through combination therapy could prevent tumor progression in EGFR+ ER+ breast cancer patients. Full article

Molecular imaging probes play a pivotal role in assaying molecular events in various physiological systems. In this study, we demonstrate a new genre of bioluminescent probes for imaging protein–protein interactions (PPIs) in mammalian cells, named the molecular association assay (MAA) probe. The MAA probe is designed to be as simple as a full-length marine luciferase fused to a protein of interest with a flexible linker. This simple fusion protein alone surprisingly works by recognizing a specific ligand, interacting with a counterpart protein of the PPI, and developing bioluminescence (BL) in mammalian cells. We made use of an artificial intelligence (AI) tool to simulate the binding modes and working mechanisms. Our AlphaFold-based analysis on the binding mode suggests that the hinge region of the MAA probe is flexible before ligand binding but becomes stiff after ligand binding and protein association. The sensorial properties of representative MAA probes, FRB-ALuc23 and FRB-R86SG, are characterized with respect to the quantitative feature, BL spectrum, and in vivo tumor imaging using xenografted mice. Our AI-based simulation of the working mechanisms reveals that the association of MAA probes with the other proteins works in a way to facilitate the substrate’s access to the active sites of the luciferase (ALuc23 or R86SG). We prove that the concept of MAA is generally applicable to other examples, such as the ALuc16- or R86SG-fused estrogen receptor ligand-binding domain (ER LBD). Considering the versatility of this conceptionally unique and distinctive molecular imaging probe compared to conventional ones, we are expecting the widespread application of these probes as a new imaging repertoire to determine PPIs in living organisms. Full article

Background/Objectives: Gelsolin (GSN) is an actin-binding protein that helps maintain neuronal structure and shape, regulates neuronal growth, and apoptosis. Our previous work demonstrated that GSN associated with estrogen receptor beta (ERβ1) in the brains of female rats, but this association was lost in advanced age. GSN was also required for ERβ1-mediated transcriptional repression at activator protein-1 (AP-1) motifs upstream of a minimal gene promoter. However, the consequences of the loss of GSN:ERβ1 protein interaction on ERβ1 nuclear translocation and transcriptional repression at AP-1 sites located within complex endogenous gene promoters remained unclear. Methods: We used immunofluorescent super resolution microscopy and luciferase reporter assays to test the hypothesis that GSN facilitates ERβ1 nuclear translocation and transcriptional repression of two genes relevant for Alzheimer Disease: APP (amyloid-beta precursor protein) and ITPKB (inositol-1,4,5-trisphosphate 3-kinase B). Results: Our results revealed the novel finding that GSN is required for ERβ1 ligand-independent nuclear translocation in neuronal cells. Moreover, we show that GSN increased APP and ITPKB promoter activity, which was repressed by ERβ1. Conclusions: Together, these data revealed the importance of the cytoskeletal protein, GSN, in regulating intracellular trafficking of nuclear receptors and demonstrate the first evidence of ERβ1 directly regulating two genes that are implicated in the progression of AD. Full article

Background and Objectives: Osteoporosis is a common chronic condition after menopause that increases the risk of fractures. In South Korea, the prevalence of osteoporosis among adults aged 50 and older is 22.4%, with 94.4% of treated patients being women, highlighting its significant impact on postmenopausal health. In this study, we examine the sales trends of osteoporosis medications in Korea from 2018 to 2023 to understand current usage patterns and market dynamics. Materials and Methods: This study is a retrospective analysis based on pre-recorded sales data from Intercontinental Marketing Services (IMS). Data covering a five-year period (2018–2023) were analyzed to examine the sales trends of osteoporosis medications, including bisphosphonates, selective estrogen receptor modulators (SERMs), parathyroid hormone analogs, denosumab, romosozumab, and others. Romosozumab, approved in November 2019, was included in the analysis. Given the nature of this study, no direct patient data or clinical interventions were involved. Results: The total market size for osteoporosis medications in South Korea reached USD 285.42 million in 2023, reflecting a 15.3% increase from 2022. Bisphosphonates, previously the dominant therapy, experienced an 11% decline in market share over five years. Meanwhile, denosumab, a receptor activator of the nuclear factor-κB ligand inhibitor, showed a remarkable growth rate of 957.6% from 2018 to 2023, surpassing bisphosphonates in their market share. Romosozumab, a newly introduced anabolic agent, accounted for 7.4% of the market, with sales increasing by 59% in 2023. Conclusions: This analysis revealed major shifts in treatment preferences, with newer drugs like denosumab and romosozumab gaining prominence over traditional bisphosphonates. These trends highlight the increasing clinical adoption of anabolic agents for high-risk patients and the impact of expanded reimbursement policies on osteoporosis management. Given the increasing use of advanced therapies, it is essential to monitor treatment access, patient adherence, and long-term clinical outcomes. Understanding these sales trends can aid healthcare professionals and policymakers in optimizing osteoporosis treatment strategies and ensuring better patient care. Full article

Background: Fibroblast growth factor (FGF) signaling plays a crucial role in several cellular functions in cancer cells. Tasurgratinib, formerly known as E7090, is an orally available FGF receptor (FGFR)1–3 selective inhibitor. Here, we present the effects of tasurgratinib on the resistance to CDK4/6 inhibitors and endocrine therapy (ET) in a preclinical model. Methods: Estrogen receptor (ER)⁺ breast cancer (BC) patient-derived xenograft (PDX) models harboring ESR1 wild-type or ESR1 mutation were used as animal models. An in vitro cell proliferation assay of ER⁺ BC cell lines treated with fulvestrant or palbociclib + fulvestrant was conducted in the presence of FGF2 and FGF10, with or without tasurgratinib. Results: Among five ER⁺ BC PDX models, OD-BRE-0438 and OD-BRE-0704 showed higher sensitivities to tasurgratinib with prior palbociclib + fulvestrant than without it. In these models, palbociclib + fulvestrant treatment upregulated the expression of several FGF ligand mRNAs. In vitro, FGF2 and FGF10 decreased the sensitivity to both fulvestrant and palbociclib + fulvestrant, which was restored by co-treatment with tasurgratinib. Consistently, fulvestrant + tasurgratinib and elacestrant + tasurgratinib showed antitumor activity in ER⁺ BC PDX models harboring ESR1 wild-type and ESR1 mutation, respectively. In these models, fulvestrant or elacestrant upregulated the expression of several FGF ligand mRNAs. Conclusions: FGF signaling plays a role in resistance to CDK4/6 inhibitors and ET in ER⁺ BC. Tasurgratinib has the potential to exhibit significant antitumor activity in combination with ET against ER⁺ BC via FGF signaling inhibition. These findings indicate the therapeutic potential of tasurgratinib in treating ER⁺ BC. Full article

Medicinal plants and natural compounds have been considered alternative therapeutic options for counteracting postmenopausal disorders thanks to their different concomitant effects, including antioxidant and anti-inflammatory properties and the regulation of hormone activity. It is important to highlight that the efficacy of medicinal plants and natural compounds increases when used in combination, thus making the development of herbal formulations rational. Therefore, the present study aimed to evaluate the phytochemical and pharmacological properties of an innovative formulation consisting of resveratrol and water extracts from Equisetum arvense, Crateagus curvisepala, Vitex agnus-castus, and Glycine max. The phenolic composition and radical scavenger properties were evaluated using chromatographic and colorimetric (ABTS) methods, whilst the limits of biocompatibility were assessed through allelopathy, the Artemia salina (brine shrimp) lethality test, and Daphnia magna cardiotoxicity assay. The protective effects were evaluated on C2C12 cell lines exposed to the pro-oxidant stimulus, which consisted of hydrogen peroxide. The gene expression of estrogen 1 (ESR1, also known as ERα) and prolactin (PRLR) receptors, interleukin 6 (IL-6), tumor necrosis factor α (TNFα), and receptor activator of nuclear factor kappa-Β ligand (RANKL) was measured. The results of the phytochemical analysis showed that the main phytochemicals were hydroxycinnamic and phenolic acids, in particular coumaric acid (7.53 µg/mL) and rosmarinic acid (6.91 µg/mL), respectively. This could explain the radical scavenger effect observed from the 2,2-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assay. According to the ecotoxicological models’ results, the formulation was revealed to be non-toxic, with a LC₅₀ value > 1 mg/mL. Therefore, a biocompatible concentration range (200–1000 µg/mL) was used in C2C12 cells, where the formulation blunted the hydrogen peroxide-induced upregulation of TNFα, IL-6, RANKL, ESR1, and PRLR. Overall, the results of this study corroborate the use of the formulation for facing the oxidative stress and inflammation, which forms the basis of the osteoclastogenic process. Full article

Background: Aromatase inhibitors-related musculoskeletal syndrome (AIMSS) is a common side effect experienced by early breast cancer patients undergoing endocrine therapy. This condition can result in medication discontinuation and a diminished quality of life. The objective of this study was to characterize AIMSS, investigate its pathogenesis, and identify potential biomarkers at both the protein and metabolic levels. Methods: We collected peripheral blood samples from 60 women diagnosed with breast cancer undergoing aromatase inhibitor therapy, of whom 30 had AIMSS and 30 did not. The samples were analyzed using four-dimensional data-independent acquisition (DIA)-based proteomics and untargeted metabolomics, employing liquid chromatography–mass spectrometry (LC–MS) on the latest platform. Results: The mean age of participants was 49.2 (11.3) years in the AIMSS group and 50.1 (11.5) years in the non-AIMSS group. There were no statistically significant differences between the two groups in terms of age, BMI, education level, clinical stage, and treatment. In total, we identified 3473 proteins and 1247 metabolites in the samples. The chemokine signaling pathway (p = 0.015), cytokine–cytokine receptor interaction (p = 0.015), complement and coagulation cascades (p = 0.004), neuroactive ligand–receptor interaction (p = 0.004), and the estrogen signaling pathway (p = 0.004) were significant enriched in differentially expressed proteins (DEPs). GnRH secretion (p < 0.001), sphingolipid signaling pathways (p < 0.001), endocrine resistance (p < 0.001), the estrogen signaling pathway (p = 0.001), endocrine and other factor-regulated calcium reabsorption (p = 0.001), dopaminergic synapse (p = 0.003), regulation of lipolysis in adipocytes (p = 0.004), biosynthesis of cofactors (p = 0.004), thyroid hormone synthesis (p = 0.008), aldosterone synthesis and secretion (p = 0.001), taurine and hypotaurine metabolism (p = 0.011), ovarian steroidogenesis (p = 0.011), and the cAMP signaling pathway (p = 0.011) were significantly enriched in differentially expressed metabolites (DEMs). Complement C3 (p = 0.004), platelet factor 4 (p = 0.015), KRT10 (p = 0.004), KRT14 (p = 0.004), beta-estradiol (p = 0.019), testosterone (p = 0.023), sphingosine (p < 0.001), and 1-stearoyl-2-arachidonoyl-sn-glycerol (p = 0.039) could be the monitoring and therapeutic targets for AIMSS. Conclusions: This study offered new insights into the mechanisms underlying musculoskeletal symptoms associated with aromatase inhibitors. It also highlighted potential biomarkers for predicting and addressing these symptoms in breast cancer patients, paving the way for improved intervention strategies. Full article

Marine cyanobacteria have gained momentum in recent years as a source of novel bioactive small molecules. This paper describes the structure elucidation and pharmacological evaluation of two new (veraguamide O (1) and veraguamide P (2)) and one known (veraguamide C (3)) analogs isolated from a cyanobacterial collection made in the Las Perlas Archipelago of Panama. We hypothesized that these compounds would be cytotoxic in cancer cell lines. The compounds were screened against HEK-293, estrogen receptor positive (MCF-7), and triple-negative breast cancer (MDA-MB-231) cells as well as against a broad panel of membrane-bound receptors. The planar structures were determined based on NMR and MS data along with a comparison to previously isolated veraguamide analogs. Phylogenetic analysis of the collection suggests it to be an Okeania sp., a similar species to the cyanobacterium reported to produce other veraguamides. Veraguamide O shows no cytotoxicity (greater than 100 μM) against ER-positive cells (MCF-7) with 13 μM IC₅₀ against MDA-MB-231 TNBC cells. Interestingly, these compounds show affinity for the sigma2/TMEM-97 receptor, making them potential leads for the development of non-toxic sigma 2 targeting ligands. Full article

Nuclear receptors (NRs) are ligand-activated transcription factors that regulate a broad array of biological processes, including inflammation, lipid metabolism, cell proliferation, and apoptosis. Among the diverse family of NRs, peroxisome proliferator-activated receptors (PPARs), estrogen receptor (ER), liver X receptor (LXR), farnesoid X receptor (FXR), retinoid X receptor (RXR), and aryl hydrocarbon receptor (AhR) have garnered significant attention for their roles in neurodegenerative diseases, particularly Alzheimer’s disease (AD). NRs influence the pathophysiology of AD through mechanisms such as modulation of amyloid-beta (Aβ) deposition, regulation of inflammatory pathways, and improvement of neuronal function. However, the dual role of NRs in AD progression, where some receptors may exacerbate the disease while others offer therapeutic potential, presents a critical challenge for their application in AD treatment. This review explores the functional diversity of NRs, highlighting their involvement in AD-related processes and discussing the therapeutic prospects of NR-targeting strategies. Furthermore, the key challenges, including the necessity for the precise identification of beneficial NRs, detailed structural analysis through molecular dynamics simulations, and further investigation of NR mechanisms in AD, such as tau pathology and autophagy, are also discussed. Collectively, continued research is essential to clarify the role of NRs in AD, ultimately facilitating their potential use in the diagnosis, prevention, and treatment of AD. Full article

Background/Objectives: Transient Receptor Potential Melastatin 8 (TRPM8) is a non-selective, Ca²⁺-permeable cation channel involved in thermoregulation and other physiological processes, such as basal tear secretion, cell differentiation, and insulin homeostasis. The activation and deactivation of TRPM8 occur through genetic modifications, channel interactions, and signaling cascades. Recent evidence suggests a significant role of TRPM8 in the hypothalamus and amygdala related to pain sensation and sexual behavior. Notably, TRPM8 has been implicated in neuropathic pain, migraines, and neurodegenerative diseases such as Parkinson’s disease. Our laboratory has identified testosterone as a high-affinity ligand of TRPM8. TRPM8 deficiency appears to influence behavioral traits in mice, like increased aggression and deficits in sexual satiety. Here, we aim to explore the pathways altered in brain tissues of TRPM8-deficient mice using the expression and methylation profiles of messenger RNA (mRNA) and long non-coding RNA (lncRNA). Specifically, we focused on brain regions integral to behavioral and hormonal control, including the olfactory bulb, hypothalamus, amygdala, and insula. Methods: RNA was isolated and purified for microarray analysis collected from male wild-type and TRPM8 knockout mice. Results: We identified various differentially expressed genes tied to multiple signaling pathways. Among them, the androgen–estrogen receptor (AR-ER) pathway, steroidogenesis pathway, sexual reward pathway, and cocaine reward pathway are particularly worth noting. Conclusions: These results should bridge the existing gaps in the knowledge regarding TRPM8 and inform potential targets for future studies to elucidate its role in the behavior changes and pathology of the diseases associated with TRPM8 activity. Full article

Breast cancer remains one of the most prevalent and lethal malignancies in women, particularly the estrogen receptor-positive (ER+) subtype, which accounts for approximately 70% of cases. Traditional endocrine therapies, including aromatase inhibitors, selective estrogen receptor degraders/antagonists (SERDs), and selective estrogen receptor modulators (SERMs), have improved outcomes for metastatic ER+ breast cancer. However, resistance to these agents presents a significant challenge. This study explores a novel therapeutic strategy involving the simultaneous inhibition of the estrogen receptor (ER) and the chaperone protein Hsp90, which is crucial for the stabilization of various oncoproteins, including ER itself. We employed a hybrid, hierarchical in silico virtual screening approach to identify new dual ER/Hsp90 inhibitors, utilizing the Biotarget Predictor Tool (BPT) for efficient multitarget screening of a large compound library. Subsequent structure-based studies, including molecular docking analyses, were conducted to further evaluate the interaction of the top candidates with both ER and Hsp90. Supporting this, molecular dynamics simulations demonstrate the high stability of the multitarget inhibitor 755435 in complex with ER and Hsp90. Our findings suggest that several small molecules, particularly compound 755435, exhibit promising potential as dual inhibitors, representing a new avenue to overcome resistance in ER+ breast cancer. Full article