Liu, Haixia; Ding, Xinyu; Liu, Linyi; Mi, Qianglong; Zhao, Quanju; Shao, YuBao; Ren, Chaowei; Chen, Jinju; Kong, Ying; Qiu, Xing; Elvassore, Nicola; Yang, Xiaobao; Yin, Qianqian; Jiang, Biao published the artcile< Discovery of novel BCR-ABL PROTACs based on the cereblon E3 ligase design, synthesis, and biological evaluation>, Recommanded Product: 4-Bromoisobenzofuran-1,3-dione, the main research area is BCR ABL PROTAC cereblon E3 ligase drug design; BCR-ABL; CRBN; Degradation; Leukemia; PROTAC.
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 mol. 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 clin. 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.
European Journal of Medicinal Chemistry published new progress about Absorption. 82-73-5 belongs to class bromides-buliding-blocks, and the molecular formula is C8H3BrO3, Recommanded Product: 4-Bromoisobenzofuran-1,3-dione.
Referemce:
Bromide – Wikipedia,
bromide – Wiktionary