William McCoull, Clare Thomson, Erin Braybrooke, Christina Chan, Nicola Colclough, Miguel A. Cortés González, Sabina Cosulich, Nichola L. Davies, Nicolas Floc’h, Ryan Greenwood, David Hargreaves, Peng Huang, Thomas A. Hunt, Tony Johnson, Peter Johnström, Jason G. Kettle, Mikhail Kondrashov, Demetrios H. Kostomiris, Songlei Li, Andrew Lister, Scott Martin, Darren McKerrecher, Neville McLean, J. Willem M. Nissink, Jonathan P. Orme, Paige Orwig, Martin J. Packer, Stuart Pearson, Lina Qin, Catarina Felisberto-Rodrigues, Adriana Savoca, Magnus Schou, Stephen Stokes, Aisha M. Swaih, Sara Talbot, Michael J. Tucker, Richard A. Ward, Emma Wadforth, Chunli Wang, Joanne Wilson, and Yawen Yang
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
Thursday, January 30, 2025
Highly Optimized CNS Penetrant Inhibitors of EGFR Exon20 Insertion Mutations
Journal of Medicinal Chemistry 2025
DOI: 10.1021/acs.jmedchem.4c02811Despite recent advances in the inhibition of EGFR (epidermal growth factor receptor), there remains a clinical need for new EGFR Exon20 insertion (Ex20Ins) inhibitors that spare EGFR WT. Herein, we report the discovery and optimization of two chemical series leading to ether 23 and biaryl 36 as potent, selective, and brain-penetrant inhibitors of Ex20Ins mutants. Building on our earlier discovery of alkyne 5 which allowed access to CNS property space for an Ex20Ins inhibitor, we utilized structure-based design to move to lower lipophilicity and lower CLint compounds while maintaining a WT selectivity margin. During optimization, aldehyde oxidase (AO) metabolism was identified as a human clearance risk, and through SAR exploration, lower AO metabolism was achieved. Potency and WT margin were optimized across a range of Ex20Ins mutants including the potential acquired resistance T790M mutant and efficacy demonstrated in an LXF2478 Ex20Ins ASV model with margin to EGFR WT in vivo.
Diethenyl Sulfoximine (DESI) as an Irreversible Lysine-Targeting Warhead Enables the Design of Covalent Allosteric EGFR Inhibitor
Huiqi Xu, Hongjin Zhang, Suyun Jia, Yanxin Tao, Quanpeng Wei, Yingao Wang, Xuechen Liu, Yuqing Zhang, Xinpeng Ning, Yuyan Shi, Can Jin, Ke D...
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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: ...