Thomas Knoepfel, Pascal Furet, Robert Mah, Nicole Buschmann, Catherine Leblanc, Sebastien Ripoche, Diana Graus-Porta, Markus Wartmann, Inga Galuba, and Robin A. Fairhurst
ACS Med. Chem. Lett., Article ASAP
DOI: 10.1021/acsmedchemlett.7b00485
As part of a project to identify FGFR4 selective inhibitors, scaffold morphing of a 2-formylquinoline amide hit identified series of 2-formylpyridine ureas (2-FPUs) with improved potency and physicochemical properties. In particular, tetrahydronaphthyridine urea analogues with cellular activities below 30 nM have been identified. Consistent with the hypothesized reversible-covalent mechanism of inhibition, the 2-FPUs exhibited slow binding kinetics, and the aldehyde, as the putative electrophile, could be demonstrated to be a key structural element for activity.
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
Research progress on covalent inhibitors targeting alkaline amino acids
Bing Zhao, Sha Xu, Shiqing Zhou, Xiangru Jiang, Ailin Jiang, Hongrui Lei, Xin Zhai Bioorganic Chemistry, 163, 2025, 108800, https://doi.org...
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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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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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Yoav Shamir, Nir London bioRxiv 2025.03.19.642201 doi: https://doi.org/10.1101/2025.03.19.642201 Recent years have seen an explosion in the...