|
|||||
|
|
Development of Rapid and Facile Solid-Phase Synthesis of PROTACs via a Variety of Binding Styles |
|
| Authors: | Hanqiao Xu Dr Takashi Kurohara Reina Takano Dr Hidetomo Yokoo Dr Norihito Shibata Dr Nobumichi Ohoka Dr Takao Inoue Prof Mikihiko Naito Dr Yosuke Demizu |
| Institution: | 1. 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 These authors contributed equally to this work.;2. National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki, Kanagawa, 210-9501 Japan;3. 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;4. National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki, Kanagawa, 210-9501 Japan Medical Chemistry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 606-0823 Japan;5. Laboratory of Targeted Protein Degradation, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 113-0033 Japan |
| 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. |
| Keywords: | BRD4 H-PGDS PROTAC protein degradation solid-phase synthesis |