Selective Targeting of Bruton Tyrosine Kinase with ACP-196: A Second-Generation Inhibitor for B-Cell Malignancies

The abstract discusses the role of B-cell receptor (BCR) signaling in B-cell malignancies, such as chronic lymphocytic leukemia (CLL), and the importance of Bruton's tyrosine kinase (BTK) in this pathway. Ibrutinib, a BTK inhibitor, has been approved for treating certain B-cell malignancies. ACP-196 is a second-generation BTK inhibitor that has shown high selectivity and efficacy in inhibiting BCR signaling in CLL cells without affecting T-cells, NK-cells, or lung epithelial cells.

ACP-196 has demonstrated a lower IC50 value against purified BTK and a lower EC50 value in a human whole-blood CD69 B-cell activation assay compared to ibrutinib. It also exhibits improved target specificity, with significant selectivity over other TEC kinase family members and no activity against EGFR, which is crucial for avoiding adverse effects associated with EGFR inhibition.

The study utilized various assays to evaluate the effects of ACP-196 on CLL patient samples, T-cell signaling, helper T-cell differentiation, CD8+ T-cell activity, NK-cell-mediated ADCC, and EGFR signaling. Results showed that ACP-196 selectively targets BTK and inhibits BCR signaling without impacting T-cell receptor signaling or NK-cell function. Additionally, it did not affect EGFR signaling in lung epithelial cells.

The findings support the potential of ACP-196 as a selective BTK inhibitor for the treatment of CLL, with Phase 3 trials currently underway. The research was funded by the NIH NCI and Acerta Pharma.