Abstract
Proto-oncogene tyrosine-protein kinase receptor RET is implicated in the development and maintenance of neurons of the central and peripheral nervous systems. Attaching activity-compromising photocleavable groups (caging) to inhibitors could allow for external spatiotemporally controlled inhibition using light, potentially providing novel information on how these kinase receptors are involved in cellular processes. Here, caged RET inhibitors were obtained from 3-substituted pyrazolopyrimidine-based compounds by attaching photolabile groups to the exocyclic amino function. The most promising compound displayed excellent inhibitory effect in cell-free, as well as live-cell assays upon decaging. Furthermore, inhibition could be efficiently activated with light in vivo in zebrafish embryos and was shown to effect motoneuron development.
Highlights
Proto-oncogene tyrosine-protein kinase receptor RET is implicated in the development and maintenance of neurons of the central and peripheral nervous systems
This is due to the non-covalent interactions with target motifs, the ability to tune their physicochemical/biological properties through organic synthesis, and convenient administration
Since kinase signalling pathways involved in cell- and organ development are inherently time- and space-dependent processes, controlling the action of the implicated enzymes in a spatiotemporal fashion would be of tremendous utility
Summary
David Bliman[1], Jesper R. Attaching activitycompromising photocleavable groups (caging) to inhibitors could allow for external spatiotemporally controlled inhibition using light, potentially providing novel information on how these kinase receptors are involved in cellular processes. The activity of a compound is masked by a photolabile group that can be cleaved off in situ using light of a specific wavelength, implying that external (photonic) control can be gained over when and where the compound is active It follows that caged effectors would represent a powerful technique for manipulating biological processes[2,3,4,5], and this scheme has been used for in situ release of for example ATP6, neurotransmitters[7,8,9,10], and phospholipids[11]. We report the design, synthesis, and biological evaluation of a caged small-molecule inhibitor of RET in cell-free and live-cell assays, as well as in zebrafish
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