Discovery of thiophen-2-ylmethylene bis-dimedone derivatives as novel WRN inhibitors for treating cancers with microsatellite instability.

Microsatellite instability (MSI) is a hypermutable condition caused by DNA mismatch repair system defects, contributing to the development of various cancer types. Recent research has identified Werner syndrome ATP-dependent helicase (WRN) as a promising synthetic lethal target for MSI cancers. Herein, we report the first discovery of thiophen-2-ylmethylene bis-dimedone derivatives as novel WRN inhibitors for MSI cancer therapy. Initial computational analysis and biological evaluation identified a new scaffold for a WRN inhibitor. Subsequent SAR study led to the discovery of a highly potent WRN inhibitor. Furthermore, we demonstrated that the optimal compound induced DNA damage and apoptotic cell death in MSI cancer cells by inhibiting WRN. This study provides a new pharmacophore for WRN inhibitors, emphasizing their therapeutic potential for MSI cancers.

Characterization of Soybean Germinated Embryo Extract as an Estrogen Receptor Subtype-Selective and Tissue-Specific Modulator.

Phytoestrogens possess beneficial effects in the management of menopausal symptoms with few side effects. Soybeans are major natural sources of isoflavones, with high estrogen receptor (ER)-ß selectivity. The objective of this study therefore was to develop a solvent-mediated extraction method for soybean germinated embryos (SGEs) and to investigate the biological activities of the extract. Ethanolic extraction yielded the SGE extract (SGEE), which had a unique composition of biologically active aglycones and soyasaponins. SGEE showed a proliferative effect in MCF7 cells and ERß-selective transcriptional activities in human embryonic kidney cells. In addition, oral administration of SGEE to ovariectomized rats resulted in the induction of ERß and estrogen-responsive genes in the uterus and a decrease in tail skin temperature and uterus weight. Our data suggest that germination and ethanolic extraction are effective measures for producing isoflavone-rich food supplements, which may be useful as alternative menopausal hormone therapy.