化学
溴尿嘧啶
蛋白质水解
连接器
小脑
嵌合体(遗传学)
DNA连接酶
泛素连接酶
酰胺
组合化学
立体化学
泛素
生物化学
DNA
酶
操作系统
基因
组蛋白
计算机科学
作者
Carola Arndt,Jacqueline Bitai,Jessica Brunner,Till Opatz,Paola Martinelli,Andreas Gollner,Kevin Rafael Sokol,Matthias Krumb
标识
DOI:10.1021/acs.jmedchem.3c01613
摘要
In this study, a one-pot synthesis via photoinduced C(sp2)–C(sp3) coupling followed by amide formation to access proteolysis targeting chimeras (PROTACs) was developed. The described protocol was studied on cereblon (CRBN)-based E3-ligase binders and (+)-JQ-1, a bromodomain inhibitor, to generate BET (bromodomain and extra terminal domain) targeting protein degraders. The generated PROTACs were profiled in vitro and tested for their degradation ability with several potent candidates identified. Upfront, the individual reactions of the one-pot transformation were carefully optimized for CRBN binder functionalization and multiple heterobifunctional linker moieties were designed and synthesized. Separate scopes detailing the C(sp2)–C(sp3) coupling and one-pot PROTAC synthesis are described in this report as well as a library miniaturization study showing the high-throughput compatibility. Overall, the developed protocol provides rapid access to PROTACs in a single process, thereby allowing efficient generation of CRBN-based PROTAC libraries.
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