Bruton's TK inhibitors: structural insights and evolution of clinical candidates.

Bruton's TK (BTK) is a promising biological target for therapeutic intervention of several diseases including inflammatory diseases and cancer/B cell malignancies. Numerous research groups are actively engaged in investigating the functions of BTK, and discovering potent and selective BTK inhibitors as drug candidates. Revealed by x-ray crystal structures with ligands of diverse chemical structures, the ability of BTK kinase domain to adopt various inactive conformations offers unique opportunities to identify highly potent and exquisitely selective inhibitors. Both reversible and covalent inhibitor approaches have yielded candidates demonstrating safety profiles and efficacies in multiple preclinical models of autoimmunity and oncology. Two BTK inhibitors have entered human clinical trials for oncology indications. Ibrutinib won the US FDA approval in November 2013 to become the first-in-class BTK inhibitor for treating mantle cell lymphoma. This encouraging outcome and the other on-going human studies could ultimately expand the utility of BTK inhibitors to broader autoimmune disease areas.