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

Affinity-driven Covalent Modulator of Glyceraldehyde-3-phosphate Dehydrogenase (GAPDH) Cascade. Angew Chem Int Ed Engl. 2018 Apr 17;: Authors: Chern J, Lu CP, Fang Z, Chang CM, Hua KF, Chen YT, Yang Ng C, Chen YS, Lam Y, Wu SH Abstract 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. PMID: 29664161 [PubMed - as supplied by publisher]
Source: Angewandte Chemie - Category: Chemistry Authors: Tags: Angew Chem Int Ed Engl Source Type: research