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- Title
Affinity‐Driven Covalent Modulator of the Glyceraldehyde‐3‐Phosphate Dehydrogenase (GAPDH) Cascade.
- Authors
Chern, Jeffy; Lu, Chun‐Ping; Fang, Zhanxiong; Chang, Ching‐Ming; Hua, Kuo‐Feng; Chen, Yi‐Ting; Ng, Cheng Yang; Chen, Yi‐Lin Sophia; Lam, Yulin; Wu, Shih‐Hsiung
- Abstract
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 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.
- Subjects
GLYCERALDEHYDEPHOSPHATE dehydrogenase; COVALENT bonds; TRADITIONAL medicine; TARGETED drug delivery; MULTIDRUG resistance; NUCLEAR magnetic resonance spectroscopy
- Publication
Angewandte Chemie, 2018, Vol 130, Issue 24, p7158
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.201801618