Integrated in silico‐in vitro analysis of systematic kinase gatekeeper mutation effects on pan‐kinase inhibitors in targeted liver cancer therapy.

Kinase‐targeted therapy has been established as a widely used strategy to treat liver cancer. However, a number of kinase gatekeeper mutations are clinically observed to cause acquired drug resistance during the therapy, which can be overcome by pan‐kinase inhibitors. Here, we create a systematic profile of pan‐kinase inhibitors against clinical kinase gatekeeper mutations in liver cancer pathogenesis by integrating computational modeling and experimental assay. With the profile we are able to identify those gatekeeper mutations that can potentially cause resistance or confer sensitivity to certain pan‐kinase inhibitors. The nine inhibitors are clustered into three groups in terms of their response profile across the investigated mutations. The group‐I and group‐II inhibitors are generally sensitized and caused with resistance by most mutations, respectively, while the group‐III inhibitors exhibit divergent response to different mutations. Structural and energetic analyses reveal that the sensitizing mutations can form additional favorable chemical forces with inhibitor ligands, while the resistant mutations would address unfavorable steric effect and conformational change on inhibitor binding. The marine natural product Hymenialdisine is found to have a general sensitivity for kinase gatekeeper mutations, which could be explored as a novel molecular lead scaffold to develop the wild type‐sparing inhibitors of kinase gatekeeper mutants. [ABSTRACT FROM AUTHOR]