Complex Crystal Structures of EGFR with Third-Generation Kinase Inhibitors and Simultaneously Bound Allosteric Ligands.

ABSTRACT: 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 comp

SUBMITTER: Niggenaber J 

PROVIDER: S-EPMC7734789 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature