Disrupted target binding with acryloyl group as potential Bcr-Abl/C-Src dual kinase inhibitor optimization strategies with maintained antitumor activity

  • Bioorg Med Chem Lett. 2025 Jan 13:119:130105. doi: 10.1016/j.bmcl.2025.130105.
Ching Lin  1 ,  Hsin-Yi Chiang  1 ,  Grace Shiahuy Chen  2 ,  Ji-Wang Chern  1 ,  Chao-Wu Yu  3
Affiliations
  • 1. National Taiwan University, School of Pharmacy, College of Medicine, Taipei 100 Taiwan.
  • 2. Department of Applied Chemistry, Providence University, Taichung 43301 Taiwan.
  • 3. National Taiwan University, School of Pharmacy, College of Medicine, Taipei 100 Taiwan. Electronic address: [email protected].
PMID: 39814085 DOI: 10.1016/j.bmcl.2025.130105
Abstract

Current CML treatments often suffer from undesired side effects. Herein we report the computation-assisted optimization of Bcr-Abl/C-Src dual kinase inhibitor. We surmised the improved toxicity profile was achieved via disrupted ligand-target binding. The development of compound 21b highlighted our strategy with ∼1000-fold weaker Bcr-Abl/C-Src inhibition but same level of antiproliferation compared to that of bosutinib. We demonstrated that the introduction of acryloyl group could serves as a potential strategy to maintain antitumor activity.

Keywords
Acryloyl group; Anticancer; Kinase inhibitor; Quinolone.
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