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

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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.

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

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Publication details

The article was received on 03 Nov 2017, accepted on 03 Feb 2018 and first published on 12 Feb 2018


Article type: Edge Article
DOI: 10.1039/C7SC04761D
Citation: Chem. Sci., 2018, Advance Article
  • Open access: Creative Commons BY license
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    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 and A. Lodola, Chem. Sci., 2018, Advance Article , DOI: 10.1039/C7SC04761D

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