National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki, Kanagawa, 210-9501, Japan.
Graduate School of Medical Life Science, Yokohama City University 1-7-29, Yokohama, Kanagawa, 230-0045, Japan.
ChemistryOpen. 2022 Jul;11(7):e202200131. doi: 10.1002/open.202200131.
Optimizing linker design is important for ensuring efficient degradation activity of proteolysis-targeting chimeras (PROTACs). Therefore, developing a straightforward synthetic approach that combines the protein-of-interest ligand (POI ligand) and the ligand for E3 ubiquitin ligase (E3 ligand) in various binding styles through a linker is essential for rapid PROTAC syntheses. Herein, a solid-phase approach for convenient PROTAC synthesis is presented. We designed azide intermediates with different linker lengths to which the E3 ligand, pomalidomide, is attached and performed facile PROTACs synthesis by forming triazole, amide, and urea bonds from the intermediates.
优化连接子设计对于确保蛋白水解靶向嵌合体（PROTAC）的降解活性至关重要。因此，开发一种直接的合成方法，通过连接子将目标蛋白配体（POI 配体）和 E3 泛素连接酶配体（E3 配体）以各种结合方式结合在一起，对于快速合成 PROTAC 至关重要。在此，提出了一种用于方便 PROTAC 合成的固相方法。我们设计了带有不同连接子长度的叠氮化物中间体，将 E3 配体泊马度胺连接到这些中间体上，并通过中间体形成三唑、酰胺和脲键，轻松地合成 PROTAC。
