Ferreira Rubén, Nilsson Jesper R, Solano Carlos, Andréasson Joakim, Grøtli Morten
Department of Chemistry and Chemical Engineering, Chalmers University of Technology, SE-412 96 Göteborg, Sweden.
Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96 Göteborg, Sweden.
Sci Rep. 2015 May 6;5:9769. doi: 10.1038/srep09769.
REarranged during Transfection (RET) is a transmembrane receptor tyrosine kinase required for normal development and maintenance of neurons of the central and peripheral nervous systems. Deregulation of RET and hyperactivity of the RET kinase is intimately connected to several types of human cancers, most notably thyroid cancers, making it an attractive therapeutic target for small-molecule kinase inhibitors. Novel approaches, allowing external control of the activity of RET, would be key additions to the signal transduction toolbox. In this work, photoswitchable RET kinase inhibitors based on azo-functionalized pyrazolopyrimidines were developed, enabling photonic control of RET activity. The most promising compound displays excellent switching properties and stability with good inhibitory effect towards RET in cell-free as well as live-cell assays and a significant difference in inhibitory activity between its two photoisomeric forms. As the first reported photoswitchable small-molecule kinase inhibitor, we consider the herein presented effector to be a significant step forward in the development of tools for kinase signal transduction studies with spatiotemporal control over inhibitor concentration in situ.
转染期间重排（RET）是一种跨膜受体酪氨酸激酶，对于中枢和外周神经系统神经元的正常发育和维持至关重要。RET的失调和RET激酶的过度活跃与多种类型的人类癌症密切相关，最显著的是甲状腺癌，这使其成为小分子激酶抑制剂有吸引力的治疗靶点。允许对RET活性进行外部控制的新方法将是信号转导工具箱的关键补充。在这项工作中，开发了基于偶氮功能化吡唑并嘧啶的光开关RET激酶抑制剂，能够对RET活性进行光子控制。最有前景的化合物表现出优异的开关特性和稳定性，在无细胞和活细胞测定中对RET具有良好的抑制作用，并且其两种光异构体形式之间的抑制活性存在显著差异。作为首次报道的光开关小分子激酶抑制剂，我们认为本文介绍的效应物是在激酶信号转导研究工具开发方面向前迈出的重要一步，能够对原位抑制剂浓度进行时空控制。
