Hydration effects on the efficacy of the Epidermal growth factor receptor kinase inhibitor afatinib.

ABSTRACT: Small molecules targeting the EGFR tyrosine kinase domain have been used with some success at treating patients with non-small cell lung cancer driven by activating mutations in the kinase domain. The initial class of inhibitors displaced ATP noncovalently but were rendered ineffective due to the development of resistance mutations in the kinase domain. These were overcome by the development of covalent inhibitors such as afatinib which also bind in the ATP pocket. However pooled analysis of two recent clinical trials LUX-3 and LUX-6 demonstrated an unprecedented overall survival benefit of afatinib over chemotherapy for the EGFR ^19del , but not the EGFR ^L858R . In the current study we use modelling and simulations to show that structural constraints in EGFR ^19de

SUBMITTER: Kannan S 

PROVIDER: S-EPMC5431542 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature