Daniela Krummenacher, Weiping He, Bernd Kuhn, Christian Schnider, Angélica Beurier, Virginie Brom, Thulase Sivasothy, Christine Marty, Andreas Tosstorff, David S. Hewings, Stefanie Mesch, Emmanuel Pinard, Mathis Brändlin, Remo Hochstrasser, Paul Westwood, Judith Rothe, Alexandra Kronenberger, Federica Morandi, Simon Gutbier, Angelika Schuler, Dominik Heer, Ludivine Esteves Gloria, Lisa Joedicke, Markus G. Rudolph, Lutz Müller, Fiona Grüninger, Karlheinz Baumann, Senthilvelrajan Kaniyappan, Nenad Manevski, and Björn Bartels
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
Tuesday, December 19, 2023
Discovery of Orally Available and Brain Penetrant AEP Inhibitors
Journal of Medicinal Chemistry 2023
DOI: 10.1021/acs.jmedchem.3c01804Alzheimer’s Disease (AD) is the most widespread form of dementia, with one of the pathological hallmarks being the formation of neurofibrillary tangles (NFTs). These tangles consist of phosphorylated Tau fragments. Asparagine endopeptidase (AEP) is a key Tau cleaving enzyme that generates aggregation-prone Tau fragments. Inhibition of AEP to reduce the level of toxic Tau fragment formation could represent a promising therapeutic strategy. Here, we report the first orthosteric, selective, orally bioavailable, and brain penetrant inhibitors with an irreversible binding mode. We outline the development of the series starting from reversible molecules and demonstrate the link between inhibition of AEP and reduction of Tau N368 fragment both in vitro and in vivo.
Rapid, potent, and persistent covalent chemical probes to deconvolute PI3Kα signaling
Lukas Bissegger, Theodora A. Constantin, Erhan Keles, Luka Raguž, Isobel Barlow-Busch, Clara Orbegozo, Thorsten Schaefer, Valentina...
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Linqi Cheng Yixian Wang, Yiming Guo, Sophie S. Zhang Han Xiao C ell Chemical Biology, 2024 Volume 31, 3, 428 - 445 https://doi.org/10.10...
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Nathalie M. Grob, Clint Remarcik, Simon L. Rössler, Jeffrey Y. K. Wong, John C. K. Wang, Jason Tao, Corey L. Smith, Andrei Loas, Stephen L. ...
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Guanghui Tang , Wei Wang , Chengjun Zhu , Huisi Huang , Peng Chen , Xuan Wang , Manyi Xu , Jie Sun , Chong-Jing Zhang , Qicai Xiao ...