Discovery of Novel Bicyclic Phenylselenyl-Containing Hybrids: An Orally Bioavailable, Potential, and Multiacting Class of Estrogen Receptor Modulators against Endocrine-Resistant Breast Cancer

Abstract

Breast cancer (BC) is a multifactorial disease and is prone to drug resistance during treatment. In this study, we described a new class of multifunctional estrogen receptor (ER) modulators ground on a prerogative indirect antagonism skeleton (OBHS, oxabicycloheptene sulfonate) of ER containing a phenylselenyl group. Compound 34b showed significant antiproliferative activities against tamoxifen-sensitive (MCF-7) and -resistant (LCC2) cells. Moreover, hexokinase 1 (HK1) was identified as a direct target of 34b. Further mechanism investigations proved that 34b induced apoptosis, which was associated with mitochondrial dysfunction caused by the synergistic effects of downregulating mitochondrial-bound HK1 protein and promoting reactive oxygen species generation. In vivo, 34b had a favorable pharmacokinetic profile with a bioavailability of 23.20% and exhibited more potent tumor suppression than tamoxifen both in MCF-7 and LCC2 tumor xenograft models. Collectively, our studies showed that 34b is a promising new multifunctional candidate compound for ERα+ BC treatment, particularly for tamoxifen-resistant BC.

Targeted Recruitment and Degradation of Estrogen Receptor α by Photothermal Polydopamine Nanoparticles for Breast Tumor Ablation

“…The specific binding of PDA‐EST and PDA‐RAL to ER α were first verified by the competitive binding experiments using coumestrol as a fluorescent tracer [ 23 ], [ 24 ] ( Figure A). Compared to nontargeted PDA, PDA‐EST and PDA‐RAL NPs could efficiently displace coumestrol from the ligand binding pocket, indicating high binding affinities to ER α .…”

Design and Structural Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High In Vivo Potency and Oral Bioavailability

“…The tumor size and body weight were monitored for the duration of the study. The tumor volume was calculated by length × width 2 × 1/2 . At the completion of the experiment, the tumor tissues were harvested and weighed to calculate the tumor growth inhibition (TGI).…”

Robust ERα-Targeted Near-Infrared Fluorescence Probe for Selective Hydrazine Imaging in Breast Cancer

“…The relative binding affinity (RBA) value of probe 1 to ERα was determined by the fluorescence polarization assay (FPA), as previously described. − Briefly, 100 μg/mL of bovine γ globulin (BGG, Solarbio), 40 nM of coumestrol (Tansoole), and 0.8 μM of human ERα LBD were diluted in 0.1 mol/L of potassium phosphate buffer (pH 7.4), followed by the addition of probe 1 solution, and then hatched for 2 h at room temperature in the dark. Finally, the fluorescence polarization values were measured using a Cytation 3 microplate reader (BioTek).…”