From identification of the BTK kinase to effective management of leukemia

Abstract

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 contrast to, for example, the SRC-family of cytoplasmic kinases, there was no obvious way in which structural alterations would yield constitutively active forms of BTK, and such mutations were also not found in leukemias or lymphomas. 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, additional inhibitors have been developed, with acalabrutinib being more selective, and recently demonstrating fewer clinical adverse effects. The antitumor 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. This quality may be crucial and bodes well for the future of BTK-modifying medicines, which have been estimated to reach annual multi-billion dollar sales in the future.

Figure 1

Linear representation of the BTK kinase domain depicting all known missense mutations causing XLA. Substituted residues in orange correspond to those reported in 2005, whereas those marked in red are the ones appearing from 2005 up until now. Coils, helixes and β-strands are color-coded, as depicted. Residues buried (B), exposed (E) or being in an intermediate (I) position according to Valiaho et al. are indicated below the amino-acid sequence. Boxed residues correspond to substitutions identified in ibrutinib- (IMBRUVICA) or acalabrutinib-treated patients, with cysteine 481 to serine substitution being the predominant change.^{, , , , , ,}

Figure 2

Chemical structure of ibrutinib (MW 440.5) and of acalabrutinib (MW 465.5), which both compete with the binding of adenosine triphosphate (ATP) to BTK. ATP (MW 507.2) is included for comparison.

Figure 3

Timeline for developments and discoveries related to the earliest description of XLA, the BTK gene cloning and the development of the first BTK inhibitor used in the clinic. The corresponding references are provided in the paragraph entitled: ‘Brief historical outlook'.

Figure 4

Meeting with Dr Ogden C Bruton (sitting) in January 1993 when the author visited him after cloning of the BTK gene. (standing) Dr Jeffrey D Thomas (left), the author, CIES (center) and Mrs Kathryn D Bruton (right). Reproduced from Smith and Notarangelo with permission from the publisher.