Bazedoxifene analogs as potential WDHD1 degraders and antitumor agents: Synthesis, evaluation and molecular dynamics simulation studies.

DNA repair is strongly associated with tumor resistance to radiotherapy and chemotherapy. WD repeat and HMG-box DNA binding protein 1 (WDHD1) is a key adaptor for homologous recombination repair of DNA, and its overexpression is relevant to the poor prognosis of many tumor patients. We previously have identified and validated bazedoxifene (BZA), which had 60% inhibitory rate on WDHD1 in MCF7 cells at 10 µM, from the Food and Drug Administration-approved compound library. Here, we initially established the binding model of BZA, synthesized and evaluated eight BZA analogs. Further, we detailed the use of molecular dynamics simulations to provide insights into the basis for activity against WDHD1. This binding mode will be instructive for the development of new WDHD1 degraders.

SREBP inhibitors: an updated patent review for 2008-present.

INTRODUCTION: Sterol regulatory element-binding proteins (SREBPs) are a family of membrane-binding transcription factors that activate genes encoding enzymes required for cholesterol and unsaturated fatty acid synthesis. Overactivation of SREBP is related to the occurrence and development of diabetes, nonalcoholic fatty liver, tumor, and other diseases. In the past period, many SREBP inhibitors have been found. AREAS COVERED: This manuscript is a patent review of SREBP inhibitors. We searched 2008 to date for all data from the US patent database (https://www.uspto.gov/) and the European patent database (https://www.epo.org/) with 'SREBP' and 'inhibitor' as keywords and analyzed the search results. EXPERT OPINION: Both synthetic and natural SREBP inhibitors have been reported. Despite the lack of cocrystal structure of SREBP inhibitor, the mechanisms of several compounds have been clarified. Importantly, some SREBP inhibitors have been proved to have good activity in preclinical studies. As the characteristics of lipid metabolism reprogramming in cardio-cerebrovascular diseases and tumors are gradually revealed, more and more attention will be focused on SREBP.

Se improves GPX4 expression and SOD activity to alleviate heat-stress-induced ferroptosis-like death in goat mammary epithelial cells.

Selenium (Se) is a vital element of life, which has an important impact on the growth, development, production performance and stress-tolerance of animals. However, it is not entirely clear that how exactly Se works during these processes. Herein, we investigate the role of Se in regulating the functions of goat mammary epithelial cells (GMECs) under heat-stress condition. We found that heat stress caused ferroptosis-like death in GMECs, manifested by a robust increase in iron ion concentration, reactive oxygen species (ROS) and cell death ratio, and a decrease in the activity of superoxide dismutase (SOD) and expression level of glutathione peroxidases 4 (GPX4). Se incubation had no obvious effect on GMEC viability, but alleviated heat-stress-induced ferroptosis-like cell death and improved GPX4 expression and SOD activity in a dose-dependent manner. Also, we found that overexpression of GPX4 could improve the activity of SOD. And Se incubation inhibited activation of mTOR signaling in heat-stress-induced GMECs, which could be eliminated by the mTOR activator MHY1485, and treatment with mTOR inhibitor AY-22989 had the same effect as Se. In conclusion, Se improves GPX4 expression and SOD activity and inhibits the activation of mTOR to alleviate heat-stress-induced ferroptosis-like death in GMECs, which may be a protective agent for heat stress in goats.