Department of Chemistry and Biochemistry, UC San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0358, USA.
Chem Commun (Camb). 2021 Jan 25;57(8):1026-1029. doi: 10.1039/d0cc05395c. Epub 2021 Jan 6.
A parallel, one-pot assembly approach to proteolysis targeting chimeras (PROTACs) is demonstrated utilizing activated esters generated in situ, and traceless Staudinger ligation chemistry. The method described allows for rapid structure-activity relationship studies of PROTAC linker variants. Two previously studied systems, cereblon and BRD4 degraders, are examined as test cases for the synthetic method. The two related strategies to assemble PROTAC linker variants discussed can accommodate the chromotographic separations capabilities of labs of many sizes and incorporates commercially available degrader building blocks, thereby easing synthetic entry into PROTAC chemical space.
本文展示了一种利用原位生成的活化酯和无痕 Staudinger 连接化学进行蛋白水解靶向嵌合体 (PROTAC) 一锅法平行合成的方法。该方法允许快速进行 PROTAC 连接变体的构效关系研究。本文选择了两个先前研究过的系统，即 cereblon 和 BRD4 降解剂，作为合成方法的测试案例。讨论的两种相关的组装 PROTAC 连接变体的策略可以适应许多规模实验室的色谱分离能力，并结合了商业可得的降解剂构建模块，从而简化了进入 PROTAC 化学空间的合成途径。
