Structure-based virtual screening and biological evaluation of novel small-molecule BTK inhibitors

Tony Eight Lin, Li Chin Sung, Min Wu Chao, Min Li, Jia Huei Zheng, Tzu Ying Sung, Jui Hua Hsieh, Chia Ron Yang, Hsueh Yun Lee, Er Chieh Cho, Kai Cheng Hsu

研究成果: 雜誌貢獻文章同行評審

摘要

Bruton tyrosine kinase (BTK) is linked to multiple signalling pathways that regulate cellular survival, activation, and proliferation. A covalent BTK inhibitor has shown favourable outcomes for treating B cell malignant leukaemia. However, covalent inhibitors require a high reactive warhead that may contribute to unexpected toxicity, poor selectivity, or reduced effectiveness in solid tumours. Herein, we report the identification of a novel noncovalent BTK inhibitor. The binding interactions (i.e. interactions from known BTK inhibitors) for the BTK binding site were identified and incorporated into a structure-based virtual screening (SBVS). Top-rank compounds were selected and testing revealed a BTK inhibitor with >50% inhibition at 10 µM concentration. Examining analogues revealed further BTK inhibitors. When tested across solid tumour cell lines, one inhibitor showed favourable inhibitory activity, suggesting its potential for targeting BTK malignant tumours. This inhibitor could serve as a basis for developing an effective BTK inhibitor targeting solid cancers.

原文英語
頁(從 - 到)226-235
頁數10
期刊Journal of Enzyme Inhibition and Medicinal Chemistry
37
發行號1
DOIs
出版狀態已發佈 - 2022

ASJC Scopus subject areas

  • 藥理
  • 藥物發現

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