Title: Photo-Brook rearrangement of acyl silanes as a strategy for photoaffinity probe design.

Authors: Page, Annika C S; Scholz, Spencer O; Keenan, Katherine N; Spradlin, Jessica N; Belcher, Bridget P; Brittain, Scott M; Tallarico, John A; McKenna, Jeffrey M; Schirle, Markus; Nomura, Daniel K; Toste, F Dean

Published In Chem Sci, (2022 Mar 30)

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.

PubMed ID: 35432890

MeSH Terms: No MeSH terms associated with this publication