Discovery of Novel Schisandrol B Simplification Derivatives as PXR Agonists to Promote Liver Regeneration
Xuan Li, Lei Zheng, Xiaowen Jiang, Haiguo Su, Chuoying Mai, Jinyi Li, Yujie Ni, Yonglin He, Wanyu Zheng, Qingqing Yu, Guofang Bi, Hui Ouyang, Shuang Hu, Chenghua Wu, Dan Li, Fengting Liang, Wenhong Zhou, Xiao Yang, Shicheng Fan, Jianhong Fang, Zhongzhen Zhou, Huichang BiAbstract
Partial hepatectomy (PHx) and liver transplantation are the most effective interventions for end-stage liver diseases, yet druggable targets that promote donor or remnant liver regeneration are critically lacking. Pregnane X receptor (PXR), a key regulator of liver regeneration, is a promising therapeutic target. Previously, we identified the natural product Schisandrol B (SolB) as a PXR agonist to promote liver regeneration. To further improve its PXR activity and selectivity, the present study performed structural simplification of SolB and identified BZZ-034, a ring-opened analogue with an isobutyl amide side chain, as a novel PXR agonist. BZZ-034 exhibited higher PXR binding affinity and stronger transcriptional efficacy than SolB, along with greater selectivity against related nuclear receptors. In vivo, BZZ-034 significantly promoted hepatomegaly and accelerated liver regeneration after PHx in mice. These findings identify BZZ-034 as a promising lead compound and demonstrate that structural simplification is an effective strategy for optimizing complex natural products.