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Photo-Brook rearrangement of acyl silanes as a new tool for photoaffinity probes design

McKenna, Jeffrey, Schirle, Markus, Tallarico, John, Brittain, Scott, Scholz, Spencer, Near, Katherine, Page, Annika, Spradlin, Jessica, Nomura, Daniel and Toste, F Dean (2022) Photo-Brook rearrangement of acyl silanes as a new tool for photoaffinity probes design. Chem Sci.


Photoaffinity labeling is a powerful tool for the identification of small molecule-protein interactions important to drug dis-covery and medicinal chemistry, but only a handful of robust photochemical warheads exist that are capable of capturing such transient interactions. Acyl silanes are an alternative car-bene precursors to diazirines, which upon irradiation, generate an α-siloxy carbene capable of inserting into polar X–H bonds, but have remained unexplored for photoaffinity labeling appli-cations. Herein, we report the synthesis of a new class of acyl silane photochemical warheads with long-UV wavelength ab-sorption and fast rates of reaction. Small molecule (+)-JQ1 and rapamycin derived acyl silanes selectively label BRD4-BD1 and FKBP12, respectively, with minimal background. Further, acyl silane (+)-JQ1 probe 16 was used in live cell proteome profiling experiments for identification of potential off-target binders and confirmation of endogenous target engagement. Site-of-modification studies showed (+)-JQ1 probe 16 inserted into T134 and K141, consistent with known previously report-ed binding data. Together, these data highlight the untapped potential of acyl silanes as a photoaffinity probe amenable to modern workflows. Further development of this class of modu-lar warheads could lead to advances in target identification and binding site mapping.

Item Type: Article
Date Deposited: 25 May 2022 00:45
Last Modified: 25 May 2022 00:45


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