Small-molecule BTK inhibitors: From discovery to clinical application

Bruton's tyrosine kinase (BTK) inhibitors constitute a promising category of small molecules for the therapy of diverse B-cell malignancies and autoimmune disorders. This review examines the journey of BTK inhibitors from their discovery to clinical development, highlighting key milestones in their design, mechanism of action, and progression through preclinical and clinical stages. Initially identified through high-throughput screening of compound libraries, early BTK inhibitors were optimized for selectivity and potency. The discovery of ibrutinib, the first Food and Drug Administration (FDA)-approved BTK inhibitor, marked a significant breakthrough, providing a new therapeutic option for patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Following this success, numerous second-generation inhibitors have been identified to address resistance mechanisms, improve pharmacokinetics, and target specific patient populations. The challenges faced during the transition from preclinical validation to clinical trials have been discussed. Additionally, ongoing trials and emerging data on novel BTK inhibitors provide insights into their evolving role in oncology and immunology. This review emphasizes the importance of rational drug design and clinical strategy in shaping the future of BTK inhibitors.