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Codrug Approach for the Potential Treatment of EML4-ALK Positive Lung Cancer

Garces, Aimie E.; Al-Hayali, Mohammed; Lee, Jong Bong; Li, Jiaxin; Gershkovich, Pavel; Bradshaw, Tracey D.; Stocks, Michael J.


Aimie E. Garces

Mohammed Al-Hayali

Jong Bong Lee

Jiaxin Li

Professor of Medicinal Chemistryand Drug Discovery


We report on the synergistic effect of PI3K inhibition with ALK inhibition for the possible treatment of EML4-ALK positive lung cancer. We have brought together ceritinib (ALK inhibitor) and pictilisib (PI3K inhibitor) into a single bivalent molecule (a codrug) with the aim of designing a molecule for slow release drug delivery that targets EML4-ALK positive lung cancer. We have joined the two drugs through a new, pH-sensitive linker where the resulting codrugs are hydrolytically stable at lower pH (pH 6.4) but rapidly cleaved at higher pH (pH 7.4). Compound (19), which was designed for optimal lung retention, demonstrated clean liberation of the drug payloads in vitro and represents a novel approach to targeted lung delivery.


Garces, A. E., Al-Hayali, M., Lee, J. B., Li, J., Gershkovich, P., Bradshaw, T. D., & Stocks, M. J. (2020). Codrug Approach for the Potential Treatment of EML4-ALK Positive Lung Cancer. ACS Medicinal Chemistry Letters, 11(3), 316-321.

Journal Article Type Article
Acceptance Date Sep 27, 2019
Online Publication Date Sep 27, 2019
Publication Date Mar 12, 2020
Deposit Date Oct 4, 2019
Publicly Available Date Sep 28, 2020
Journal ACS Medicinal Chemistry Letters
Print ISSN 1948-5875
Electronic ISSN 1948-5875
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 11
Issue 3
Pages 316-321
Keywords Synergy, Cancer resistance, Bivalent ligands, Codrugs, pH-dependent controlled release
Public URL
Publisher URL
Additional Information This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Medicinal Chemistry Letters, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see


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