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Abstract
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.
Highlights
We have used this approach to control the activity of a REarranged during Transfection (RET) tyrosine kinase receptor by harnessing the isomerization-induced structural changes of a photochromic azobenzene-derived pyrazolopyrimidine unit
We hypothesized that the RET kinase domain would not tolerate the inhibitor in the Z-form (Fig. 1b), leading to a design strategy focused on incorporation of the photoswitchable unit in the 3-position of the pyrazolopyrimidine scaffold
We have presented the design, synthesis, and photophysical/biological characterization of azobenzene-derived photoswitches aiming at photocontrolled RET kinase inhibition
Summary
We have used this approach to control the activity of a REarranged during Transfection (RET) tyrosine kinase receptor by harnessing the isomerization-induced structural changes of a photochromic azobenzene-derived pyrazolopyrimidine unit. Azobenzenes form one of the largest and most studied classes of photochromic molecules and are the most widely used photoswitches in biological applications[13,14,15,16,17] The reasons behind this include the ease of synthesis, relatively high photostationary states and isomerization yields, as well as low rate of photodecomposition. We hypothesized that the RET kinase domain would not tolerate the inhibitor in the Z-form (Fig. 1b), leading to a design strategy focused on incorporation of the photoswitchable unit in the 3-position of the pyrazolopyrimidine scaffold. Further synthetic efforts yielded 3 and 4 (Fig. 2) from the azobenzene family
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