Emerging small-molecule inhibitors of the Bruton's tyrosine kinase (BTK): Current development

Therapy based on Bruton's tyrosine kinase (Btk) inhibitors one of the major treatment options currently recommended for lymphoma patients. The first generation of Btk Inhibitor, Ibrutinib, achieved remarkable progress in the treatment of B-cell malignancies, but still has problems with drug-resistance or off-target induced serious side effects. Therefore, numerous new Btk inhibitors were developed to address this unmet medical need. In parallel, the effect of Btk inhibitors against immune-related diseases has been evaluated in clinical trials. This review summarizes recent progress in the research and development of Btk inhibitors, with a focus on structural characteristics and structure-activity relationships. The structure-refinement process of representative pharmacophores as well as their effects on binding affinity, biological activity and pharmacokinetics profiles were analyzed. The advantages and disadvantages of reversible/irreversible Btk inhibitors and their potential implications were discussed to provide a reference for the rational design and development of novel potent Btk inhibitors.

Bruton’s tyrosine kinase; Kinase inhibitor; Lymphoma; Structure-activity relationship.