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.

Abstract

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.

Citation

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. https://doi.org/10.1021/acsmedchemlett.9b00378

• 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
• Electronic ISSN: 1948-5875
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 11
• Issue: 3
• Pages: 316-321
• DOI: https://doi.org/10.1021/acsmedchemlett.9b00378
• Keywords: Synergy, Cancer resistance, Bivalent ligands, Codrugs, pH-dependent controlled release
• Public URL: https://nottingham-repository.worktribe.com/output/2750132
• Publisher URL: https://pubs.acs.org/doi/10.1021/acsmedchemlett.9b00378
• 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 https://pubs.acs.org/doi/10.1021/acsmedchemlett.9b00378
• Contract Date: Oct 4, 2019