期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 223, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2021.113645
关键词
PROTAC; CRBN; Leukemia; BCR-ABL; Degradation
资金
- National Natural Science Foundation of China (NSFC) [81702600]
- Shanghai Sailing Program [17YF1412200]
- Shanghai Natural Science Foundation [19ZR1433600]
Protein degradation through CRBN-recruiting PROTACs has shown promising potential in targeting oncogenic fusion protein BCR-ABL, providing a potential therapeutic strategy for chronic myeloid leukemia.
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. (C) 2021 Elsevier Masson SAS. All rights reserved.
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