453565-93-0Relevant academic research and scientific papers
Start Selective and Rigidify: The Discovery Path toward a Next Generation of EGFR Tyrosine Kinase Inhibitors
Engelhardt, Harald,B?se, Dietrich,Petronczki, Mark,Scharn, Dirk,Bader, Gerd,Baum, Anke,Bergner, Andreas,Chong, Eugene,D?bel, Sandra,Egger, Georg,Engelhardt, Christian,Ettmayer, Peter,Fuchs, Julian E.,Gerstberger, Thomas,Gonnella, Nina,Grimm, Andreas,Grondal, Elisabeth,Haddad, Nizar,Hopfgartner, Barbara,Kousek, Roland,Krawiec, Mariusz,Kriz, Monika,Lamarre, Lyne,Leung, Joyce,Mayer, Moriz,Patel, Nitinchandra D.,Simov, Biljana Peric,Reeves, Jonathan T.,Schnitzer, Renate,Schrenk, Andreas,Sharps, Bernadette,Solca, Flavio,Stadtmüller, Heinz,Tan, Zhulin,Wunberg, Tobias,Zoephel, Andreas,McConnell, Darryl B.
supporting information, p. 10272 - 10293 (2019/11/21)
The epidermal growth factor receptor (EGFR), when carrying an activating mutation like del19 or L858R, acts as an oncogenic driver in a subset of lung tumors. While tumor responses to tyrosine kinase inhibitors (TKIs) are accompanied by marked tumor shrinkage, the response is usually not durable. Most patients relapse within two years of therapy often due to acquisition of an additional mutation in EGFR kinase domain that confers resistance to TKIs. Crucially, oncogenic EGFR harboring both resistance mutations, T790M and C797S, can no longer be inhibited by currently approved EGFR TKIs. Here, we describe the discovery of BI-4020, which is a noncovalent, wild-type EGFR sparing, macrocyclic TKI. BI-4020 potently inhibits the above-described EGFR variants and induces tumor regressions in a cross-resistant EGFRdel19 T790M C797S xenograft model. Key was the identification of a highly selective but moderately potent benzimidazole followed by complete rigidification of the molecule through macrocyclization.
Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
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, (2008/06/13)
The present invention provides compounds and pharmaceutical compositions that act as antagonists at metabotropic glutamate receptors, and that are useful for treating neurological diseases and disorders. Methods of preparing the compounds also are disclosed.
