L718Q mutant EGFR escapes covalent inhibition by stabilizing a non-reactive conformation of the lung cancer drug osimertinib.
L718Q mutant EGFR escapes covalent inhibition by stabilizing a non-reactive conformation of the lung cancer drug osimertinib.
复制标题
DOI：
10.1039/c7sc04761d
复制
发表时间：
2018-03-14
期刊：
影响因子：
8.4
通讯作者：
Lodola A
中科院分区：
文献类型：
--
作者：
Callegari D;Ranaghan KE;Woods CJ;Minari R;Tiseo M;Mor M;Mulholland AJ;Lodola A
Impact of L718Q mutation on the inhibitory activity of osimertinib on EGFR revealed by free-energy simulations. 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.
登录
查看更多内容
影响因子：
7.3
作者：
Finlay, M. Raymond V.;Anderton, Mark;Wrigley, Gail L.
通讯作者：
Wrigley, Gail L.
影响因子：
3.7
作者：
Lodola A;Branduardi D;De Vivo M;Capoferri L;Mor M;Piomelli D;Cavalli A
通讯作者：
Cavalli A
影响因子：
3.5
作者：
Michalczyk, Anja;Klueter, Sabine;Rauh, Daniel
通讯作者：
Rauh, Daniel
DOI：
10.1158/1078-0432.ccr-14-2789
发表时间：
2015-09-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Ercan D;Choi HG;Yun CH;Capelletti M;Xie T;Eck MJ;Gray NS;Jänne PA
通讯作者：
Jänne PA
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML