L718Q mutant EGFR escapes covalent inhibition by stabilizing a non-reactive conformation of the lung cancer drug osimertinib

D Callegari, K E Ranaghan, C J Woods, R Minari, M Tiseo, M Mor, A J Mulholland, A Lodola

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Abstract

Osimertinib is a third-generation inhibitor approved for the treatment of non-small cell lung cancer. It overcomes resistance to first-generation inhibitors by incorporating an acrylamide group which alkylates Cys797 of EGFR T790M. The mutation of a residue in the P-loop (L718Q) was shown to cause resistance to osimertinib, but the molecular mechanism of this process is unknown. Here, we investigated the inhibitory process for EGFR T790M (susceptible to osimertinib) and EGFR T790M/L718Q (resistant to osimertinib), by modelling the chemical step (i.e., alkylation of Cys797) using QM/MM simulations and the recognition step by MD simulations coupled with free-energy calculations. The calculations indicate that L718Q has a negligible impact on both the activation energy for Cys797 alkylation and the free-energy of binding for the formation of the non-covalent complex. The results show that Gln718 affects the conformational space of the EGFR-osimertinib complex, stabilizing a conformation of acrylamide which prevents reaction with Cys797.
Original languageEnglish
Pages (from-to)2740-2749
Number of pages10
JournalChemical Science
Volume9
Issue number10
Early online date12 Feb 2018
DOIs
Publication statusPublished - 14 Mar 2018

Structured keywords

  • BrisSynBio
  • Bristol BioDesign Institute

Keywords

  • Synthetic Biology

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