Molecular analysis and systematic profiling of allosteric inhibitor response to clinically significant epidermal growth factor receptor missense mutations in non‐small cell lung cancer

Abstract

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 muta-

An unconventional gatekeeper mutation sensitizes inositol hexakisphosphate kinases to an allosteric inhibitor

“…The first scenario appears more likely, as a similar phenomenon was observed for an allosteric EGFR inhibitor that was 1000-fold more potent against the acquired T790M gatekeeper resistance mutant, compared to the WT kinase. 70,83 The EGFR inhibitor also exhibited direct binding interaction with the mutated gatekeeper residue, similar to our observations with FMP-201300. In general, these allosteric inhibitors preferably target an inactive conformation of protein kinases, which often confers selectivity owing to their greater structural heterogeneity compared to the corresponding active conformations.…”

An unconventional gatekeeper mutation sensitizes inositol hexakisphosphate kinases to an allosteric inhibitor

“…It remains unclear if the gatekeeper mutation caused this displacement or merely increased the conformational flexibility of the αC helix to facilitate the induced fit of FMP-201300. The first scenario appears more likely, as a similar phenomenon was observed for an allosteric EGFR inhibitor that was 1000-fold more potent against the acquired T790M gatekeeper resistance mutant, compared to the WT kinase (Jia et al, 2016;Zhao et al, 2021). The EGFR inhibitor also exhibited direct binding interaction with the mutated gatekeeper residue, similar to our observations with FMP-201300.…”