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.

Development of Kinase‐Centric Drugs: A Computational Perspective

“…Using structure-based virtual screening, Lin et al recently found novel small molecule inhibitors of Bruton tyrosine kinase (BTK). [97] Binding contacts within BTK were found by docking known inhibitors with probable biological activity, and these proteinligand interactions were then exploited for virtual screening of NCI database compounds (0.28 million). Using the Lipinski Rule of Five and PAINS substructures, the database compounds were filtered, and the remaining compounds were docked into the active site of BTK.…”