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
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.
Chem Sci. 2022 Mar 11;13(13):3851-3856. doi: 10.1039/d2sc00426g. eCollection 2022 Mar 30.
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 Pr-substituted acyl silane with superior photolabeling and minimal thermal background labeling compared to other substituted acyl silanes. Further, small molecule (+)-JQ1- and rapamycin-derived Pr 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.
光亲和标记（PAL）是一种用于识别对药物发现和药物化学至关重要的非共价小分子 - 蛋白质相互作用的强大工具，但这种方法仅限于一小部分强大的光交联剂。因此，非常需要鉴定能够进行共价靶标捕获的新的光反应性基序。在此，我们报告了基于酰基硅烷的紫外触发的1,2 - 光布鲁克重排的一类新型PAL弹头的设计、合成和评估，迄今为止尚未将其用于PAL工作流程。在细胞裂解物中对一系列探针进行照射，结果显示与其他取代的酰基硅烷相比，一种Pr取代的酰基硅烷具有优异的光标记性能和最小的热背景标记。此外，小分子（+）-JQ1和雷帕霉素衍生的Pr酰基硅烷分别显示出以最小的背景选择性标记重组BRD4 - BD1和FKBP12。总之，这些数据突出了酰基硅烷作为光亲和标记的新型、可调节支架的未开发潜力。
