2. Academic Validation
  3. Discovery and characterization of novel potent BCR-ABL degraders by conjugating allosteric inhibitor

Discovery and characterization of novel potent BCR-ABL degraders by conjugating allosteric inhibitor

  • Eur J Med Chem. 2022 Dec 15;244:114810. doi: 10.1016/j.ejmech.2022.114810.
Haixia Liu 1,  Qianglong Mi 2,  Xinyu Ding 3,  Chencen Lin 1,  Linyi Liu 4,  Chaowei Ren 3,  ShuTing Shen 3,  YuBao Shao 5,  Jinju Chen 6,  Yongqi Zhou 6,  Liting Ji 6,  Heqiao Zhang 6,  Fang Bai 7,  Xiaobao Yang 8,  Qianqian Yin 9,  Biao Jiang 10
Affiliations

Affiliations

  • 1 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China; School of Physical Science and Technology, ShanghaiTech University, Shanghai, 201210, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 2 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 3 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 4 Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China.
  • 5 Department of Histology and Embryology, Anhui Medical University, Hefei, 230032, China.
  • 6 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China.
  • 7 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China. Electronic address: baifang@shanghaitech.edu.cn.
  • 8 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China; Gluetacs Therapeutics (Shanghai) Co., Ltd., 99 Haike Road, Zhangjiang Hi-Tech Park, Shanghai, 201210, China. Electronic address: yang.xiaobao@gluetacs.com.
  • 9 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China. Electronic address: yinqq@shanghaitech.edu.cn.
  • 10 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, 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: 36306539 DOI: 10.1016/j.ejmech.2022.114810
Abstract

The oncogenic fusion protein Bcr-Abl is the driving force of leukemogenesis in chronic myeloid leukemia (CML). Despite the great advance in CML treatment through the application of tyrosine kinase inhibitors (TKIs) against Bcr-Abl, disease recurrence after TKI discontinuation and clinical resistance mainly due to Bcr-Abl mutations continue to be an issue. Herein we report our efforts to synthesize a novel series of CRBN-recruiting proteolysis-targeting chimeras (PROTACs) targeting Bcr-Abl based on the allosteric inhibitor asciminib. Our efforts have led to the discovery of compound 30 (SIAIS100) through extensive SAR studies by the optimization of linker parameters as well as linker attachment points of both target-binding warhead and CRBN ligands, which exhibited the most potent degradative activity with a DC50 value of 2.7 nM and Dmax of 91.2% against Bcr-Abl and has an IC50 value of 12 nM in Bcr-Abl + K562 cells. The binding model and the stability evaluation of 30-induced ternary complex formation were also elucidated through computational simulations. Furthermore, 30 induced sustained and robust Bcr-Abl degradation and maintained the efficacy for 96 h post-washout. Moreover, the proteomics analysis showed that 30 degraded Bcr-Abl and three CRBN's neo-substrates, including IKZF1, IKZF3, and ZFP91. Additionally, 30 also exerted degradative activity against a panel of clinically relevant resistance-conferring mutations of Bcr-Abl, including gatekeeper mutation T315I, several single mutations associated with TKI resistance, and certain highly resistant compound mutations. Our study provided a deeper understanding of the development of PROTACs targeting Bcr-Abl and novel potential therapeutic agents for CML treatment.

Keywords

Allosteric inhibitor; BCR-ABL; CML; CRBN; Drug resistance; PROTACs.

Figures
Products