BTK inhibitors: past, present, and future.

One of the most successful and highly developed drug targets in cancer is Bruton's tyrosine kinase (BTK). Remarkable basic and translational studies have led to the clinical approval of several generations of small-molecule BTK inhibitors. Recent discovery of kinase-deficient BTK inhibitor resistance mutations sheds light on still undiscovered roles of BTK in B cell receptor signaling. Noncovalent BTK inhibitors represent potential future frontline treatment options in chronic lymphocytic leukemia (CLL). New dual-binding BTK inhibitors and BTK degraders represent the future of BTK targeting. Successful development of BTK inhibitors in cancer has led to new applications in other conditions such as autoimmune disease. Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment landscape for B cell lymphomas such as chronic lymphocytic leukemia (CLL). The first-in-class BTK inhibitor ibrutinib has recently been succeeded by covalent BTK inhibitors that are safer but still face challenges of resistance mutations. The noncovalent BTK inhibitor pirtobrutinib was recently approved for relapsed and refractory CLL, and whether noncovalent BTK inhibitors will supplant covalent BTK inhibitors as upfront treatment options either alone or in combination will be determined. Meanwhile, newer BTK inhibitors and BTK degraders are vying for their place in the potential future landscape of B cell cancers as well as autoimmune diseases. This review will cover the latest progress in BTK inhibitor development and where the field is moving in light of these recent discoveries. [ABSTRACT FROM AUTHOR]