A blog highlighting recent publications in the area of covalent modification of proteins, particularly relating to covalent-modifier drugs. @CovalentMod on Twitter and @covalentmod@mstdn.science on Mastodon
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.
Covalent drug discovery using sulfur(VI) fluoride exchange warheads
Huang Huang, Lyn H. Jones Expert Opinion on Drug Discovery , 2023 https://doi.org/10.1080/17460441.2023.2218642 Covalent drug discovery has ...
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Zhao, Z.; Bourne, P. E. ChemRxiv 2022 . https://doi.org/10.26434/chemrxiv-2022-nlb0m Kinase-targeted drug discovery for cancer therapy ha...
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Wang, S.; Hadisurya, M.; Tao, W. A.; Dykhuizen, E.; Krusemark, C. ChemRxiv 2022 . https://doi.org/10.26434/chemrxiv-2022-tvgn1 Targeted co...
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Jian Ding, Guo Li, Hejun Liu, Lulu Liu, Ying Lin, Jingyan Gao, Guoqiang Zhou, Lingling Shen, Mengxi Zhao, Yanyan Yu, Weihui Guo, Ulrich Homm...