Inhibitors of BTK and ITK: State of the New Drugs for Cancer, Autoimmunity and Inflammatory Diseases

• Published in: Scandinavian journal of immunology Vol. 78; no. 2; pp. 130 - 139
• Main Authors: Vargas, L., Hamasy, A., Nore, B. F., E. Smith, C. I.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.08.2013
• Subjects: Agammaglobulinaemia Tyrosine Kinase; Agammaglobulinemia - drug therapy; Agammaglobulinemia - enzymology; Agammaglobulinemia - genetics; Agammaglobulinemia - pathology; Antineoplastic Agents - therapeutic use; Autoimmunity - drug effects; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; Epstein-Barr virus; Epstein-Barr Virus Infections - drug therapy; Epstein-Barr Virus Infections - enzymology; Epstein-Barr Virus Infections - genetics; Epstein-Barr Virus Infections - pathology; Gene Expression Regulation, Neoplastic - drug effects; Genetic Diseases, X-Linked - drug therapy; Genetic Diseases, X-Linked - enzymology; Genetic Diseases, X-Linked - genetics; Genetic Diseases, X-Linked - pathology; Humans; Inflammation - prevention & control; Lymphoma - drug therapy; Lymphoma - enzymology; Lymphoma - genetics; Lymphoma - pathology; Medicin och hälsovetenskap; Protein Kinase Inhibitors - therapeutic use; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Pyrazoles - therapeutic use; Pyrimidines - therapeutic use; Signal Transduction - drug effects; Small Molecule Libraries - therapeutic use; T-Lymphocytes - drug effects; T-Lymphocytes - immunology
• ISSN: 0300-9475; 1365-3083; 1365-3083
• DOI: 10.1111/sji.12069

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.