Design, Synthesis, and Evaluation of Potent, Selective, and Bioavailable AKT Kinase Degraders
| العنوان: | Design, Synthesis, and Evaluation of Potent, Selective, and Bioavailable AKT Kinase Degraders |
|---|---|
| المؤلفون: | Li Wang, Yudao Shen, Jian Jin, Jia Xu, Kaitlyn M. Cahuzac, Xian Chen, Xufen Yu, Ramon Parsons, Jing Liu, Ling Xie |
| المصدر: | J Med Chem |
| بيانات النشر: | American Chemical Society (ACS), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Biological Availability, Article, Piperazines, Mice, Structure-Activity Relationship, chemistry.chemical_compound, Cell Line, Tumor, Drug Discovery, Animals, Humans, Phosphatidylinositol, Protein Kinase Inhibitors, Protein kinase B, PI3K/AKT/mTOR pathway, biology, Kinase, Cereblon, Proteolysis targeting chimera, Ubiquitin ligase, Cell biology, Pyrimidines, chemistry, Drug Design, biology.protein, Molecular Medicine, Signal transduction, Proto-Oncogene Proteins c-akt |
| الوصف: | The serine/threonine kinase AKT functions as a critical node of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (m-TOR) signaling pathway. Aberrant activation and overexpression of AKT are strongly correlated with numerous human cancers. To date, only two AKT degraders with no structure–activity relationship (SAR) results have been reported. Through extensive SAR studies on various linkers, E3 ligase ligands, and AKT binding moieties, we identified two novel and potent AKT proteolysis targeting chimera (PROTAC) degraders: von Hippel–Lindau (VHL)-recruiting degrader 13 (MS98) and cereblon (CRBN)-recruiting degrader 25 (MS170). These two compounds selectively induced robust AKT protein degradation, inhibited downstream signaling, and suppressed cancer cell proliferation. Moreover, these two degraders exhibited good plasma exposure levels in mice through intraperitoneal injection. Overall, our comprehensive SAR studies led to the discovery of degraders 13 and 25, which are potentially useful chemical tools to investigate biological and pathogenic functions of AKT in vitro and in vivo. |
| تدمد: | 1520-4804 0022-2623 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::282a33b7e211ac3e81e57d9f184f81e4 https://doi.org/10.1021/acs.jmedchem.1c01476 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....282a33b7e211ac3e81e57d9f184f81e4 |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 15204804 00222623 |
|---|