부산대학교 도서관

Human epidermal growth factor receptor (EGFR) is an attractive anti‐non‐small cell lung cancer (anti‐NSCLC) druggable target, but many traditional adenosine triphosphate (ATP)‐competitive EGFR inhibitors have been clinically observed to eventually establish acquired resistance due to kinase mutations. Allosteric inhibitors represent a new direction of EGFR‐targeted therapy, which have been successfully developed since 2016 to overcome the widely occurring kinase drug‐resistant mutations T790M/C797S [Jia Y, et al. Nature 2016; 534: 129–132]. In this study, a systematic inhibitor response‐to‐mutation profile of 11 reported EGFR allosteric inhibitors against 17 clinically significant EGFR missense mutations in NSCLC was created by integrating computational analyses and kinase assays, from which we were able to identify a number of representative mutation/inhibitor pairs with sensitization and deactivation. It is unraveled that most mutations have only a moderate or modest effect on inhibitor binding, while few mutations located within or nearby the kinase's allosteric site can cause strong sensitization or deactivation to allosteric inhibitors; thus they can influence the inhibitor binding substantially by forming or breaking noncovalent interactions between them. In particular, the gatekeeper mutation T790M and constitutively activated mutation L858R were observed to effectively improve the inhibitory potency of allosteric inhibitors, whereas the gain‐of‐function mutation T854A was revealed to considerably reduce inhibitory activity by breaking a geometrically perfect hydrogen bond. In addition, we also found that the allosteric inhibitor‐addressed conformational change in EGFR kinase domain has only a marginal effect on ATP binding, suggesting that allosteric inhibitors do not use the substrate‐regulatory strategy to suppress kinase activity; instead, they just shift the EGFR conformational equilibrium from active to inactive states by inducing a displacement in kinase's αC‐helix. [ABSTRACT FROM AUTHOR]