Targets for Ibrutinib Beyond B Cell Malignancies

<jats:title>Abstract</jats:title><jats:p>Ibrutinib (Imbruvica<jats:sup>™</jats:sup>) is an irreversible, potent inhibitor of Bruton's tyrosine kinase (<jats:styled-content style="fixed-case">BTK</jats:styled-content>). Over the last few years, ibrutinib has developed from a promising drug candidate to being approved by <jats:styled-content style="fixed-case">FDA</jats:styled-content> for the treatment of three B cell malignancies, a truly remarkable feat. Few, if any medicines are monospecific and ibrutinib is no exception; already during ibrutinib's initial characterization, it was found that it could bind also to other kinases. In this review, we discuss the implications of such interactions, which go beyond the selective effect on <jats:styled-content style="fixed-case">BTK</jats:styled-content> in B cell malignancies. In certain cases, the outcome of ibrutinib treatment likely results from the combined inhibition of <jats:styled-content style="fixed-case">BTK</jats:styled-content> and other kinases, causing additive or synergistic, effects. Conversely, there are also examples when the clinical outcome seems unrelated to inhibition of <jats:styled-content style="fixed-case">BTK</jats:styled-content>. Thus, more specifically, adverse effects such as enhanced bleeding or arrhythmias could potentially be explained by different interactions. We also predict that during long‐term treatment bone homoeostasis might be affected due to the inhibition of osteoclasts. Moreover, the binding of ibrutinib to molecular targets other than <jats:styled-content style="fixed-case">BTK</jats:styled-content> or effects on cells other than B cell‐derived malignancies could be beneficial and result in new indications for clinical applications.</jats:p>