Discovery of novel BCR-ABL PROTACs based on the cereblon E3 ligase design, synthesis, and biological evaluation

Eur J Med Chem. 2021 Nov 5:223:113645. doi: 10.1016/j.ejmech.2021.113645.

Haixia Liu ¹, Xinyu Ding ², Linyi Liu ³, Qianglong Mi ⁴, Quanju Zhao ⁵, YuBao Shao ⁶, Chaowei Ren ⁴, Jinju Chen ⁵, Ying Kong ⁵, Xing Qiu ⁷, Nicola Elvassore ⁵, Xiaobao Yang ⁸, Qianqian Yin ⁹, Biao Jiang ¹⁰

Affiliations

1 School of Physical Science and Technology, ShanghaiTech University, Shanghai, 201210, China; Shanghai Institute for Advanced Immunochemical Studies, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
2 Shanghai Institute for Advanced Immunochemical Studies, China; School of Life Science and Technology, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
3 Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, School of Pharmaceutical Science, University of South China, Hengyang City, 421001, China.
4 Shanghai Institute for Advanced Immunochemical Studies, China; School of Life Science and Technology, China.
5 Shanghai Institute for Advanced Immunochemical Studies, China.
6 Department of Histology and Embryology, Anhui Medical University, Hefei, 230032, China.
7 CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China.
8 Shanghai Institute for Advanced Immunochemical Studies, China. Electronic address: xiaobaoyoung@126.com.
9 Shanghai Institute for Advanced Immunochemical Studies, China. Electronic address: yinqq@shanghaitech.edu.cn.
10 Shanghai Institute for Advanced Immunochemical Studies, China; CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China. Electronic address: jiangbiao@shanghaitech.edu.cn.

PMID: 34217059 DOI: 10.1016/j.ejmech.2021.113645

Abstract

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.

Keywords

BCR-ABL; CRBN; Degradation; Leukemia; PROTAC.

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