A blog highlighting recent publications in the area of covalent modification of proteins, particularly relating to covalent-modifier drugs. @CovalentMod on Twitter, @covalentmod@mstdn.science on Mastodon, and @covalentmod.bsky.social on BlueSky
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.
Allosteric Covalent Inhibitors of the STAT3 Transcription Factor from Virtual Screening
Tibor Viktor Szalai, Vincenzo di Lorenzo, Nikolett Péczka, Levente M. Mihalovits, László Petri, Qirat F. Ashraf, Elvin D. de Araujo, Viktor ...
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Design, synthesis and biological evaluation of the activity-based probes for FGFR covalent inhibitorDandan Zhu, Zijian Zheng, Huixin Huang, Xiaojuan Chen, Shuhong Zhang, Zhuchu Chen, Ting Liu, Guangyu Xu, Ying Fu, Yongheng Chen, European Jo...
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DOI Ansgar Oberheide, Maxime van den Oetelaar, Jakob Scheele, Jan Borggräfe, Semmy Engelen, Michael Sattler, Christian Ottmann, ...
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Özge Ünsal, Z. Selin Bacaksiz, Vladislav Khamraev, Vittorio Montanari, Martin Beinborn, and Krishna Kumar ACS Chemical Biology 2024 DOI: ...