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Affinity‐Driven Covalent Modulator of the Glyceraldehyde‐3‐Phosphate Dehydrogenase (GAPDH) Cascade
Author(s) -
Chern Jeffy,
Lu ChunPing,
Fang Zhanxiong,
Chang ChingMing,
Hua KuoFeng,
Chen YiTing,
Ng Cheng Yang,
Chen YiLin Sophia,
Lam Yulin,
Wu ShihHsiung
Publication year - 2018
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201801618
Subject(s) - glyceraldehyde 3 phosphate dehydrogenase , cascade , glyceraldehyde , chemistry , dehydrogenase , covalent bond , biochemistry , enzyme , chromatography , organic chemistry
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 reveal that ( Z )‐(+)‐isochaihulactone ( 1 ) exhibited significant inhibition against multiple‐drug‐resistant (MDR) cancer cell lines and mice xenografts. NMR spectroscopy showed that 1 resisted an off‐target thiolate, thus indicating that 1 was a target covalent inhibitor (TCI). By identifying the pharmacophore of 1 (α,β‐unsaturated moiety), a probe derived from 1 was designed and synthesized for TCI‐oriented activity‐based proteome profiling. By MS/MS and computer‐guided molecular biology approaches, an affinity‐driven Michael addition of the noncatalytic C247 residue of GAPDH was found to control the “ON/OFF” switch of apoptosis through non‐canonically nuclear GAPDH translocation, which bypasses the common apoptosis‐resistant route of MDR cancers.