Horbert Rebecca, Pinchuk Boris, Davies Paul, Alessi Dario, Peifer Christian
Pharmaceutical Chemistry, Christian Albrechts University , Gutenbergstraße 76, 24118 Kiel, Germany.
MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee , Dow Street, Dundee DD1 5EH, U.K.
ACS Chem Biol. 2015 Sep 18;10(9):2099-107. doi: 10.1021/acschembio.5b00174. Epub 2015 Jul 10.
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.
在本研究中，我们报道了维莫非尼的新型光可激活笼形前药。这种激酶抑制剂是首个被批准用于BRAF突变型黑色素瘤个性化治疗的药物，并且在临床研究中显示出令人瞩目的效果。然而，严重副作用和耐药性的出现表明迫切需要创新的治疗方法。为克服这些局限性，我们将可光去除的保护基团引入维莫非尼。总体而言，这种笼形概念可对由紫外线触发的分子激活进行空间和时间控制。因此，在肿瘤组织中可能以较小的全身效应达到更高的抑制剂浓度。我们的研究描述了用作药理学工具的笼形维莫非尼前药的首次开发。我们研究了它们的光化学特性和光激活。体外评估在激酶和细胞试验中证明了预期的功能丧失和光依赖性的疗效恢复。所报道的维莫非尼光前药代表了癌症研究中新型药理学方法的强大生物学工具。
