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

Haixia Liu, Qianglong Mi, Xinyu Ding, Chencen Lin, Linyi Liu, Chaowei Ren, Shu Ting Shen, Yu Bao Shao, Jinju Chen, Yongqi Zhou, Liting Ji, Heqiao Zhang, Fang Bai, Xiaobao Yang, Qianqian Yin, Biao Jiang

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish
Article number114810
JournalEuropean Journal of Medicinal Chemistry
Volume244
DOIs
StatePublished - 15 Dec 2022
Externally publishedYes

Keywords

  • Allosteric inhibitor
  • BCR-ABL
  • CML
  • CRBN
  • Drug resistance
  • PROTACs

Fingerprint

Dive into the research topics of 'Discovery and characterization of novel potent BCR-ABL degraders by conjugating allosteric inhibitor'. Together they form a unique fingerprint.

Cite this