Affinity‐driven Covalent Modulator of Glyceraldehyde‐3‐phosphate Dehydrogenase (GAPDH) Cascade

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  Shih-Hsiung Wu

Angewandte Chemie, 2018

doi: 10.1002/ange.201801618

Traditional medicines provide a fertile ground to explore potent lead compounds; yet, their transformation into modern drugs is fraught with challenges in deciphering the target that is mechanistically valid for its biological activity. Herein we revealed Z‐(+)‐isochaihulactone 1 exhibited significant inhibition against MDR cancer cell lines and mice xenografts. By NMR spectroscopy, 1 was shown to resist to an off‐targeting thiolate, thus giving 1 a target covalent inhibitor‐like (TCI) property. By identifying the pharmacophore of 1 (α,β‐unsaturated moiety), a 1‐derived probe was designed and synthesized for TCI‐oriented activity‐based proteome profiling (TCI‐ABPP). With MS/MS and computer‐guided molecular biology approaches, we elucidated that an affinity‐driven Michael addition of the noncatalytic C247 of GAPDH controlled the "ON/OFF" switch of apoptosis through non‐canonically nuclear GAPDH translocation, which bypasses the common apoptosis‐resistant route of MDR cancers.