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


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.

SUBMITTER: Garces AE 

PROVIDER: S-EPMC7073869 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Garces Aimie E AE   Al-Hayali Mohammed M   Lee Jong Bong JB   Li Jiaxin J   Gershkovich Pavel P   Bradshaw Tracey D TD   Stocks Michael J MJ  

ACS medicinal chemistry letters 20190927 3


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  ...[more]

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