title: Inhibitors of BTK and ITK: state of the new drugs for cancer, autoimmunity and inflammatory diseases.
abstract: BTK and ITK are cytoplasmic tyrosine kinases of crucial importance for B and T cell development, with loss-of-function mutations causing X-linked agammaglobulinemia and susceptibility to severe, frequently lethal, Epstein-Barr virus infection, respectively. Over the last few years, considerable efforts have been made in order to develop small-molecule inhibitors for these kinases to treat lymphocyte malignancies, autoimmunity or allergy/hypersensitivity. The rationale is that even if complete lack of BTK or ITK during development causes severe immunodeficiency, inactivation after birth may result in a less severe phenotype. Moreover, therapy can be transient or only partially block the activity of BTK or ITK. Furthermore, a drug-induced B cell deficiency is treatable by gamma globulin substitution therapy. The newly developed BTK inhibitor PCI-32765, recently renamed Ibrutinib, has already entered several clinical trials for various forms of non-Hodgkin lymphoma as well as for multiple myeloma. Experimental animal studies have demonstrated highly promising treatment effects also in autoimmunity. ITK inhibitors are still under the early developmental phase, but it can be expected that such drugs will also become very useful. In this study, we present BTK and ITK with their signalling pathways and review the development of the corresponding inhibitors.
authors.affiliation: Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Vargas
authors.forename: A
authors.initials: A
authors.lastname: Hamasy
authors.forename: B F
authors.initials: BF
authors.lastname: Nore
authors.forename: C I E
authors.initials: CI
authors.lastname: Smith
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015551:Autoimmunity / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D020031:Epstein-Barr Virus Infections / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D040181:Genetic Diseases, X-Linked / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000517:prevention & control; D008223:Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D054852:Small Molecule Libraries; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C080813:emt protein-tyrosine kinase; D000225:Adenine