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Insight into resistance mechanism of anaplastic lymphoma kinase to alectinib and JH-VIII-157-02 caused by G1202R solvent front mutation

Authors Wang H, Wang Y, Guo W, Du B, Huang X, Wu R, Yang B, Lin X, Wu Y

Received 24 July 2017

Accepted for publication 19 December 2017

Published 9 May 2018 Volume 2018:12 Pages 1183—1193

DOI https://doi.org/10.2147/DDDT.S147104

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Amy Norman

Peer reviewer comments 3

Editor who approved publication: Dr Qiongyu Guo


Han Wang,1–3 Yao Wang,1–3 Wentao Guo,4 Bin Du,1–3 Xiaobing Huang,1–3 Riping Wu,1–3 Baoyu Yang,1–3 Xiaoyan Lin,1–3,5 Yilan Wu6

1Department of Medical Oncology, Fujian Medical University Union Hospital, Fuzhou, People’s Republic of China; 2Stem Cell Research Institute, Fujian Medical University, Fuzhou, People’s Republic of China; 3Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou, People’s Republic of China; 4School of Pharmacy, Wenzhou Medical University, Wenzhou, People’s Republic of China; 5Graduate School of Education, Fujian Medical University, Fuzhou, People’s Republic of China; 6School of Nursing, Fujian University of Traditional Chinese Medicine, Fuzhou, People’s Republic of China

Background: Mutated anaplastic lymphoma kinase (ALK) drives the development of advanced non-small cell lung cancer (NSCLC). Most reported small-molecule inhibitors targeting the ALK domain do not display good inhibition of the G1202R solvent front mutation. The solvent front mutation was assumed to hinder drug binding. However, a different fact could be uncovered by the simulations reported in this study through a structural analog of alectinib (JH-VIII-157-02), which demonstrated potent effects against the G1202R mutation.
Methods: Molecular docking, conventional molecular dynamics (MD) simulations, free energy calculations, and umbrella sampling (US) simulations were carried out to make clear the principles of the binding preferences of alectinib and JH-VIII-157-02 toward ALKWT and the ALK G1202R (ALKG1202R) mutation.
Results: JH-VIII-157-02 has similar binding affinities to both ALKWT and ALKG1202R whereas it has has a much lower binding affinity for alectinib to ALKG1202R. Analysis of individual energy terms indicate the major variation involves the van der Waals and entropy terms. Structural analysis reveals that the conformational change of the ATP-binding glycine-rich loop was primarily responsible for the alectinib resistance, not JH-VIII-157-02. In addition, US simulations prove JH-VIII-157-02 has similar dissociative processes from both ALKWT and ALKG1202R, while alectinib is more easily dissociated from ALKG1202R than from ALKWT, thus indicating lesser residence time.
Conclusion: Both the binding affinity and the drug residence time should be emphasized in rational drug design to overcome the G1202R solvent front mutation in ALK resistance.

Keywords: ALK, G1202R, alectinib, JH-VIII-157-02, theoretical study, resistance mechanisms

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