Photo-Brook rearrangement of acyl silanes as a strategy for photoaffinity probe design |
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Authors: | Annika C S Page Spencer O Scholz Katherine N Keenan Jessica N Spradlin Bridget P Belcher Scott M Brittain John A Tallarico Jeffrey M McKenna Markus Schirle Daniel K Nomura F Dean Toste |
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Institution: | Department of Chemistry, University of California, Berkeley California 94720 USA.; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, University of California, Berkeley California 94720 USA ; Innovative Genomics Institute, University of California, Berkeley California 94720 USA ; Novartis Institute for BioMedical Research, Cambridge Massachusetts 02139 USA ; Department of Molecular and Cellular Biology, University of California, Berkeley California 94720 USA |
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Abstract: | Photoaffinity labeling (PAL) is a powerful tool for the identification of non-covalent small molecule–protein interactions that are critical to drug discovery and medicinal chemistry, but this approach is limited to only a small subset of robust photocrosslinkers. The identification of new photoreactive motifs capable of covalent target capture is therefore highly desirable. Herein, we report the design, synthesis, and evaluation of a new class of PAL warheads based on the UV-triggered 1,2-photo-Brook rearrangement of acyl silanes, which hitherto have not been explored for PAL workflows. Irradiation of a series of probes in cell lysate revealed an iPr-substituted acyl silane with superior photolabeling and minimal thermal background labeling compared to other substituted acyl silanes. Further, small molecule (+)-JQ1- and rapamycin-derived iPr acyl silanes were shown to selectively label recombinant BRD4-BD1 and FKBP12, respectively, with minimal background. Together, these data highlight the untapped potential of acyl silanes as a novel, tunable scaffold for photoaffinity labeling.Irradiation initiated 1,2-photo Brook rearrangement of acyl silanes generated α-siloxycarbene intermediates that were used for photoaffinity labeling. Optimization of the acyl silane group produced a probe capable of capturing small molecule–protein interactions. |
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