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

被引：3

作者：

Garces, Aimie E. ^{[1
]}

Al-Hayali, Mohammed ^{[1
]}

Lee, Jong Bong ^{[1
]}

Li, Jiaxin ^{[1
]}

Gershkovich, Pavel ^{[1
]}

Bradshaw, Tracey D. ^{[1
]}

Stocks, Michael J. ^{[1
]}

机构：

[1] Univ Pk Nottingham, Ctr Biomol Sci, Sch Pharm, Nottingham NG7 2RD, England

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2020年 / 11卷 / 03期

基金：

英国医学研究理事会;

关键词：

Synergy; cancer resistance; bivalent ligands; codrugs; pH-dependent controlled release; ANAPLASTIC LYMPHOMA KINASE; RECEPTOR TYROSINE KINASE; DRUG-COMBINATION; ALK; INHIBITOR; IDENTIFICATION; RESISTANCE; CERITINIB; DISCOVERY; GDC-0941;

D O I：

10.1021/acsmedchemlett.9b00378

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：316 / 321

页数：6

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