Open AccessComplex Crystal Structures of EGFR with Third-Generation Kinase Inhibitors and Simultaneously Bound Allosteric Ligands
Author(s) -
Janiiggenaber,
Leonie Heyden,
Tobias Grabe,
Matthias Müller,
Jonas Lategahn,
Daniel Rauh
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00472
Subject(s) - osimertinib , allosteric regulation , t790m , epidermal growth factor receptor , tyrosine kinase , chemistry , small molecule , kinase , cancer research , mutant , pharmacology , receptor , medicine , biochemistry , erlotinib , gefitinib , gene
Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) and currently the gold-standard for the treatment of patients suffering from non-small cell lung cancer (NSCLC) harboring T790M-mutated epidermal growth factor receptor (EGFR). The outcome of the treatment, however, is limited by the emergence of the C797S resistance mutation. Allosteric inhibitors have a different mode of action and were developed to overcome this limitation. However, most of these innovative molecules are not effective as a single agent. Recently, mutated EGFR was successfully addressed with osimertinib combined with the allosteric inhibitor JBJ-04-125-02, but surprisingly, structural insights into their binding mode were lacking. Here, we present the first complex crystal structures of mutant EGFR in complex with third-generation inhibitors such as osimertinib and mavelertinib in the presence of simultaneously bound allosteric inhibitors. These structures highlight the possibility of further combinations targeting EGFR and lay the foundation for hybrid inhibitors as next-generation TKIs.