Garces Aimie E, Al-Hayali Mohammed, Lee Jong Bong, Li Jiaxin, Gershkovich Pavel, Bradshaw Tracey D, Stocks Michael J
School of Pharmacy, Centre for Biomolecular Sciences, University Park Nottingham, Nottingham NG7 2RD, U.K.
ACS Med Chem Lett. 2019 Sep 27;11(3):316-321. doi: 10.1021/acsmedchemlett.9b00378. eCollection 2020 Mar 12.
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 (), 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.
我们报告了PI3K抑制与ALK抑制联合使用对可能治疗EML4-ALK阳性肺癌的协同作用。我们将色瑞替尼（ALK抑制剂）和匹地利斯（PI3K抑制剂）组合成一个单一的二价分子（一种协同药物），目的是设计一种用于靶向EML4-ALK阳性肺癌的缓释药物递送分子。我们通过一种新的pH敏感连接子将这两种药物连接起来，所得的协同药物在较低pH值（pH 6.4）下具有水解稳定性，但在较高pH值（pH 7.4）下会迅速裂解。为实现最佳肺部滞留而设计的化合物（）在体外显示出药物有效载荷的完全释放，代表了一种靶向肺部递送的新方法。
