Saturday, April 28, 2018

Affinity‐driven Covalent Modulator of Glyceraldehyde‐3‐phosphate Dehydrogenase (GAPDH) Cascade

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

Angewandte Chemie, 2018

doi: 10.1002/ange.201801618

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 revealed Z‐(+)‐isochaihulactone 1 exhibited significant inhibition against MDR cancer cell lines and mice xenografts. By NMR spectroscopy, 1 was shown to resist to an off‐targeting thiolate, thus giving 1 a target covalent inhibitor‐like (TCI) property. By identifying the pharmacophore of 1 (α,β‐unsaturated moiety), a 1‐derived probe was designed and synthesized for TCI‐oriented activity‐based proteome profiling (TCI‐ABPP). With MS/MS and computer‐guided molecular biology approaches, we elucidated that an affinity‐driven Michael addition of the noncatalytic C247 of GAPDH controlled the "ON/OFF" switch of apoptosis through non‐canonically nuclear GAPDH translocation, which bypasses the common apoptosis‐resistant route of MDR cancers.

Oncogenic KRAS G12C: Kinetic and Redox Characterization of Covalent Inhibition

Minh V. Huynh, Derek Parsonage, Tom E. Forshaw, Venkat R. Chirasani, G. Aaron Hobbs, Hanzhi Wu, Jingyun Lee, Cristina M. Furdui, Leslie B. P...