Affinity‐Driven Covalent Modulator of the Glyceraldehyde‐3‐Phosphate Dehydrogenase (GAPDH) Cascade. Issue 24 (14th May 2018)

• Record Type: Journal Article
• 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
• Is Part Of: Angewandte Chemie international edition. Volume 57:Issue 24(2018)
• Page Start: 7040
• Page End: 7045
• Publication Date: 2018-05-14
• Subjects: asymmetric synthesis -- castration-resistant prostate cancer -- covalent inhibitors -- enzymes -- multiple-drug resistance; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201801618
• Languages: English
• ISSNs: 1433-7851

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 that1 resisted an off‐target thiolate, thus indicating that1 was a target covalent inhibitor (TCI). By identifying the pharmacophore of1 (α, β‐unsaturated moiety), a probe derived from1 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. Abstract : Overcoming resistance : A new class of inhibitors that target the noncatalytic C247 residue of GAPDH in an affinity‐driven manner to initiate SIAH1‐dependent apoptosis and androgen‐receptor degradation has been discovered (see picture). The affinity‐driven Michael addition of isochaihulactone was found to control the "ON/OFF" switch of apoptosis by a mechanism that bypasses the common apoptosis‐resistant route of multiple‐drug‐resistant cancers.