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

Abstract

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.

Keywords:

• Virtual screening
• kinase inhibitor
• BTK
• solid tumours
• small-molecule inhibitors

Author contributions

TEL, LCS, ECC, and KCH conceived and designed the experiments. TEL, MWC, ML, JHZ, CRY, HYL, and ECC prepared the materials and performed the experiments. TEL, LCS, TYS, JHH, and KCH analysed the computational data and results. The manuscript was organised and written by TEL, ECC, and KCH.

Disclosure statement

The authors declare that there are no conflicts of interest.

Additional information

Funding

This work was supported by the Taipei Medical University –Shuang Ho Hospital [Grant No. 105TMU-SHH-27] and the Ministry of Science and Technology, Taiwan [MOST 108–2320-B-038–058-MY3]. This research was also partially supported by Health and welfare surcharge of tobacco products [MOHW110-TDU-B-212–144020] and “TMU Research Centre of Cancer Translational Medicine” from the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan.