| Title | Design, Synthesis, and Evaluation of Highly Potent FAK-Targeting PROTACs |
| Authors | Gao, Hongying Wu, Yue Sun, Yonghui Yang, Yiqing Zhou, Guangbiao Rao, Yu |
| Affiliation | Tsinghua Univ, Sch Pharmaceut Sci, MOE Key Lab Prot Sci, MOE Key Lab Bioorgan Phosphorus Chem & Chem Biol, Beijing 100084, Peoples R China Peking Univ, Joint Ctr Life Sci, Tsinghua Univ, Beijing 100084, Peoples R China Chinese Acad Med Sci & Peking Union Med Coll, Natl Canc Ctr, State Key Lab Mol Oncol, Natl Clin Res Ctr Canc,Canc Hosp, Beijing 100021, Peoples R China |
| Keywords | FOCAL ADHESION KINASE E3 UBIQUITIN LIGASE INHIBITOR SCAFFOLD INSIGHT CANCER |
| Issue Date | 8-Oct-2020 |
| Publisher | ACS MEDICINAL CHEMISTRY LETTERS |
| Abstract | Focal adhesion kinase (FAK), a cytoplasmic protein tyrosine kinase, exerts kinase-dependent enzymatic functions and kinase-independent scaffolding functions, both of which are crucial in cancer development, early embryonic development, and reproduction. However, previous efforts for FAK blocking mainly focus on kinase inhibitors. Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that allow direct post-translational knockdown of proteins via ubiquitination of a target protein by E3 ubiquitin ligase and subsequent proteasomal degradation. Here, we designed and synthesized a FAK PROTAC library with FAK inhibitor (PF562271 or VS6063) and CRBN E3 ligand. A novel FAK-targeting PROTAC, FC-11, showed a rapid and reversible FAK degradation with a picomolar of DC50 in various cell lines in vitro, which imply that FAK-PROTACs could be useful as expand tools for studying functions of FAK in biological system and as potential therapeutic agents. |
| URI | http://hdl.handle.net/20.500.11897/593004 |
| ISSN | 1948-5875 |
| DOI | 10.1021/acsmedchemlett.9b00372 |
| Indexed | SCI(E) |
| Appears in Collections: | 生命科学学院 |
