Farnesoid X receptor (FXR) ligands have been extensively pursued to treat metabolic disorders, liver and bile diseases, among others. Starting from two widely distributed natural product chemotypes, chalcone and pentacyclic triterpene, we discovered several groups of FXR ligands, including 7-substituted chalcone, polyoxygenated benzofuran, benzoxepine, 3- and 12-substitued oleanolic acid analogs, etc. After extensive structural optimization, with the assistance of molecular modeling, some highly potent antagonists with IC50 as much as 10-8 M have been found,. They are tested in diabetes and NASH mice and rat models, exhibiting improved hyperglycemia, hyperlipidemia, and other phenotypes. Such pharmacological activities are made through the selective modulation on FXR and its downstream genes, including BSEP, SHP, CYP7A1, SREBP-1c, G6P and PEPCK involved in bile acid, glucose and lipid metabolism. Some FXR antagonists have also been found to inhibit cell proliferation and metastasis of non small cell lung cancer (NSCLC) in an FXR dependent way, showing the potential as targeted therapeutic agent for high FXR expressing NSCLC.

Discovery and optimization of natural products based selective FXR antagonists with the potential in metabolic disease and tumor therapy

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.