Development of Rapid and Facile Solid‐Phase Synthesis of PROTACs via a Variety of Binding Styles
Hanqiao Xu, Takashi Kurohara, Reina Takano, Hidetomo Yokoo, Norihito Shibata, Nobumichi Ohoka, Takao Inoué, Mikihiko Naito, Yosuke Demizu
Abstract
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.