Affinity-Driven Covalent Modulator of the Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) Cascade

被引：7

作者：

Chern, Jeffy ^{[1
,2
,3
]}

Lu, Chun-Ping ^{[4
]}

Fang, Zhanxiong ^{[5
]}

Chang, Ching-Ming ^{[2
]}

Hua, Kuo-Feng ^{[6
]}

Chen, Yi-Ting ^{[3
]}

Ng, Cheng Yang ^{[5
]}

Chen, Yi-Lin Sophia ^{[6
]}

Lam, Yulin ^{[5
]}

Wu, Shih-Hsiung ^{[1
,2
,3
]}

机构：

[1] Acad Sinica, Inst Biol Chem, Taipei, Taiwan

[2] Acad Sinica, Taiwan Int Grad Program, Chem Biol & Mol Biophys Program, Taipei, Taiwan

[3] Natl Taiwan Univ, Dept Chem, Taipei, Taiwan

[4] Fu Jen Catholic Univ, Dept Food Sci, Taipei, Taiwan

[5] Natl Univ Singapore, Dept Chem, Singapore, Singapore

[6] Natl Ilan Univ, Dept Biotechnol & Anim Sci, Ilan, Taiwan

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2018年 / 57卷 / 24期

关键词：

asymmetric synthesis; castration-resistant prostate cancer; covalent inhibitors; enzymes; multiple-drug resistance; PROSTATE-CANCER; ANDROGEN RECEPTOR; CELLS; ENZALUTAMIDE; CHEMOTHERAPY; SURVIVAL; NMR;

D O I：

10.1002/anie.201801618

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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 (,-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.

引用

页码：7040 / 7045

页数：6

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