Discovery of novel BCR-ABL PROTACs based on the cereblon E3 ligase design, synthesis, and biological evaluation
Autor: | Haixia Liu, Xing Qiu, Linyi Liu, Biao Jiang, Xiaobao Yang, Xinyu Ding, Ren Chaowei, Kong Ying, Yubao Shao, Nicola Elvassore, Quanju Zhao, Qianglong Mi, Chen Jinju, Yin Qianqian |
---|---|
Rok vydání: | 2021 |
Předmět: |
Ubiquitin-Protein Ligases
Transplantation Heterologous Dasatinib Fusion Proteins bcr-abl Protein degradation Ligands 01 natural sciences 03 medical and health sciences Mice Structure-Activity Relationship hemic and lymphatic diseases Neoplasms Drug Discovery medicine Animals Humans Lenalidomide Protein Kinase Inhibitors 030304 developmental biology Cell Proliferation Pharmacology 0303 health sciences biology 010405 organic chemistry Chemistry Cereblon Organic Chemistry Myeloid leukemia General Medicine Pomalidomide Fusion protein 0104 chemical sciences Ubiquitin ligase Thalidomide Drug Design Proteolysis biology.protein Cancer research K562 Cells medicine.drug K562 cells Half-Life |
Zdroj: | European journal of medicinal chemistry. 223 |
ISSN: | 1768-3254 |
Popis: | Protein degradation is a promising strategy for drug development. Proteolysis-targeting chimeras (PROTACs) hijacking the E3 ligase cereblon (CRBN) exhibit enormous potential and universal degradation performance due to the small molecular weight of CRBN ligands. In this study, the CRBN-recruiting PROTACs were explored on the degradation of oncogenic fusion protein BCR-ABL, which drives the pathogenesis of chronic myeloid leukemia (CML). A series of novel PROTACs were synthesized by conjugating BCR-ABL inhibitor dasatinib to the CRBN ligand including pomalidomide and lenalidomide, and the extensive structure-activity relationship (SAR) studies were performed focusing on optimization of linker parameters. Therein, we uncovered that pomalidomide-based degrader 17 (SIAIS056), possessing sulfur-substituted carbon chain linker, exhibits the most potent degradative activity in vitro and favorable pharmacokinetics in vivo. Besides, degrader 17 also degrades a variety of clinically relevant resistance-conferring mutations of BCR-ABL. Furthermore, degrader 17 induces significant tumor regression against K562 xenograft tumors. Our study indicates that 17 as an efficacious BCR-ABL degrader warrants intensive investigation for the future treatment of BCR-ABL+ leukemia. |
Databáze: | OpenAIRE |
Externí odkaz: |