Targeting Bruton’s Tyrosine Kinase in CLL: Selectivity, Resistance Mechanisms, and Emerging Therapeutic Strategies

Kinases are highly explored drug targets due to their central role in cell growth, differentiation, and cell death, as well as their relationship to cancer initiation and progression. However, with more than 500 kinases in the human kinome and significant structural similarities among them, kinases present a major selectivity challenge. Bruton’s tyrosine kinase (BTK), a highly studied kinase, plays an important role in the B-cell receptor pathway. Overexpression of BTK in B cells has been linked to the development of B-cell lymphomas, like chronic lymphocytic leukemia (CLL), as well as certain autoimmune diseases. For this reason, BTK is an attractive therapeutic target. In this review, we will provide a summary of the design of irreversible inhibitors, reversible inhibitors, and Proteolysis-targeting chimera (PROTAC) degraders targeting BTK. We will include crystal structures of compounds bound to BTKWT and provide a review of how the design of these inhibitors and PROTACs leads to a more selective inhibition and degradation of BTK. With the emergence of identified BTK resistance mutations, alternative strategies beyond established BTK inhibitors are fundamental for designing more selective inhibitors and degraders that can overcome resistance.