Photoactivatable Prodrugs of Antimelanoma Agent Vemurafenib

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• 作者：Rebecca Horbert ; Boris Pinchuk ; Paul Davies ; Dario Alessi ; Christian Peifer
• 刊名：ACS Chemical Biology
• 出版年：2015
• 出版时间：September 18, 2015
• 年：2015
• 卷：10
• 期：9
• 页码：2099-2107
• 全文大小：479K
• ISSN：1554-8937

文摘

In this study, we report on novel photoactivatable caged prodrugs of vemurafenib. This kinase inhibitor was the first approved drug for the personalized treatment of BRAF-mutated melanoma and showed impressive results in clinical studies. However, the occurrence of severe side effects and drug resistance illustrates the urgent need for innovative therapeutic approaches. To conquer these limitations, we implemented photoremovable protecting groups into vemurafenib. In general, this caging concept provides spatial and temporal control over the activation of molecules triggered by ultraviolet light. Thus, higher inhibitor concentrations in tumor tissues might be reached with less systemic effects. Our study describes the first development of caged vemurafenib prodrugs useful as pharmacological tools. We investigated their photochemical characteristics and photoactivation. In vitro evaluation proved the intended loss-of-function and the light-dependent recovery of efficacy in kinase and cellular assays. The reported vemurafenib photo prodrugs represent a powerful biological tool for novel pharmacological approaches in cancer research.