title: Targets for Ibrutinib Beyond B Cell Malignancies.
abstract: Ibrutinib (Imbruvica™) is an irreversible, potent inhibitor of Bruton's tyrosine kinase (BTK). Over the last few years, ibrutinib has developed from a promising drug candidate to being approved by FDA 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 BTK in B cell malignancies. In certain cases, the outcome of ibrutinib treatment likely results from the combined inhibition of BTK and other kinases, causing additive or synergistic, effects. Conversely, there are also examples when the clinical outcome seems unrelated to inhibition of BTK. 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 BTK or effects on cells other than B cell-derived malignancies could be beneficial and result in new indications for clinical applications.
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Berglöf
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Hamasy
authors.affiliation: Center for Hematology and Regenerative Medicine, Karolinska Institutet, and Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Meinke
authors.affiliation: Department of Hematology, Karolinska University Hospital Solna, Stockholm, Sweden.|Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Palma
authors.affiliation: Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Krstic
authors.affiliation: Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: R
authors.initials: R
authors.lastname: Månsson
authors.affiliation: Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Kimby
authors.affiliation: Department of Hematology, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Österborg
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: C I E
authors.initials: CI
authors.lastname: Smith
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001281:Atrial Fibrillation / Q000139:chemically induced; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy; D008232:Lymphoproliferative Disorders / Q000188:drug therapy*; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy; D010010:Osteoclasts / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D008258:Waldenstrom Macroglobulinemia / Q000188:drug therapy
chemical_list: D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D000225:Adenine