Affinity‐Driven Covalent Modulator of the Glyceraldehyde‐3‐Phosphate Dehydrogenase (GAPDH) Cascade |
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| 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 Shih‐Hsiung Wu |
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| Affiliation: | 1. Institute of Biological Chemistry, Academia Sinica, Taiwan;2. Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan;3. Department of Chemistry, National Taiwan University, Taipei, Taiwan;4. Department of Food Science, Fu Jen Catholic University, Taipei, Taiwan;5. Department of Chemistry, National University of Singapore, Singapore;6. Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan |
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| 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. |
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| Keywords: | asymmetric synthesis castration-resistant prostate cancer covalent inhibitors enzymes multiple-drug resistance |
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