BTK is a cytoplasmic protein-tyrosine kinase, whose corresponding gene was isolated in the early 1990s. BTK was initially identified by positional cloning of the gene causing X-linked agammaglobulinemia and independently in a search for new kinases. Given the phenotype of affected patients, namely lack of B-lymphocytes and plasma cells with the ensuing inability to mount humoral immune responses, BTK inhibitors were anticipated to have beneficial effects on antibody-mediated pathologies, such as autoimmunity. In 2007, the first efficient inhibitor, ibrutinib, was reported and soon became approved both in the United States and in Europe for the treatment of three B-cell malignancies, mantle cell lymphoma, chronic lymphocytic leukemia and Waldenström’s macroglobulinemia. Over the past few years, more than ten additional inhibitors have been developed, several of which are in clinical trials. The anti-tumor mechanism is also not related to mutations in BTK. Instead tumor residency in lymphoid organs is inhibited, making these drugs highly versatile. BTK is one of the only 10 human kinases that carry a cysteine in the adenosine triphosphate-binding cleft. As this allows for covalent, irreversible inhibitor binding, it provides these compounds with a highly advantageous character. Some BTK inhibitors instead bind reversibly, which could be of importance, since when resistance develops, drugs not affected by the resistance mutations are likely to already exist. The aim of the project is to generate a detailed update of the ongoing studies on the new BTK inhibitors.
Smith, C.I. Edvard and Rula Zain. 2019. Therapeutic Oligonucleotides: State of the Art. Annual Review of Pharmacology and Toxicology, 59(1), 605–630. https://doi.org/10.1146/annurev-pharmtox-010818-021050