Solving the acting target and molecular mechanism of Z-(+)-isochaihulactone
Traditional medicines provide a fertile ground to explore potent "lead" compounds with desired effects; yet, their transformation into modern drugs is often fraught with challenges in deciphering the target that is mechanistically valid for its biological activity. The research team led by Dr. Shih-Hsiung Wu, a Distinguished Research Fellow in the Institute of Biological Chemistry, and collaborators in National Ilan University and National University of Singapore determined the acting target and molecular mechanism of Z-(+)-isochaihulactone (active lignin from a traditional Chinese medicine - Nan Chai Hu, Bupleurum scorzonerifolium) and whether the compound can serve as a promising lead compound for future drug development. The paper has been published in Angewandte Chemie International Edition on June 11, 2018.
Firstly, we revealed that compound markedly inhibits the growth of some drug-resistant prostate cancer cell lines and mice xenografts. By NMR spectroscopy, the compound was shown to resist to an off-targeting thiolate, thus giving compound a targeted covalent inhibitor-like (TCI) property. By identifying the pharmacophore of compound (α,β-unsaturated moiety), a compound-derived probe was designed and synthesized for TCI-oriented activity-based proteome profiling (TCI-ABPP). With MS/MS and computer-guided molecular biology approach, we elucidated that the noncatalytic C247 of GAPDH was indispensable in controlling the “ON/OFF” switch of apoptosis and ligand binding domain (LBD)-independent androgen receptor (AR) degradation. Taken together, these findings shed new light on the obstacle existed in castration-resistant prostate cancer (CRPC) treatment.
The Full research article: https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.201801618
Authors : Jeffy Chern, Chun-Ping Lu, Zhanxiong Fang, Ching-Ming Chang, Kuo-Feng Hua, Yi-Ting Chen, Cheng Yang Ng, Yi-Lin Sophia Chen, Yulin Lam,* and Shih-Hsiung Wu*
Updated : 2018.06.12