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.

Ibrutinib interferes with the cell-mediated anti-tumor activities of therapeutic CD20 antibodies: implications for combination therapy

“…9,29 Different mutations in Btk or in downstream signaling effector molecules in neoplastic B cells, as well as B-cell anergy, may determine sensitivity to the cytotoxic effect of ibrutinib, 13,30,31 but this was not further investigated here. Rather, we examined the effect of ibrutinib on the induction of direct cell death by anti-CD20 antibodies.…”

“…8,10,11 Ibrutinib has recently been approved as a single agent for the treatment of refractory and relapsed CLL and mantle cell lymphoma, and combinations of ibrutinib with other drugs, including anti-CD20 antibodies, are currently being tested in phase 2-3 clinical trials in the same diseases (www.clinicaltrials.gov). [12][13][14][15][16][17] The molecular target of ibrutinib, Btk, is a Tec family tyrosine ©2014 Ferrata Storti Foundation. This is an open-access paper.…”

Targets for Ibrutinib Beyond B Cell Malignancies

“…This active site occupancy inhibits the subsequent phosphorylation of BTK, phospholipase C γ 2 (PLC γ 2), AKT and ERK and abolishes the BCR signalling downstream of BTK both in vitro and in vivo 8. Furthermore, inhibition of BTK impairs proliferation, survival and induces apoptosis of malignant B cells 9.…”

Targeting Interleukin-2-inducible T-cell Kinase (ITK) and Resting Lymphocyte Kinase (RLK) Using a Novel Covalent Inhibitor PRN694

“…In some settings, it appears that ITK and RLK are redundant signaling molecules because overexpression of RLK in ITK Ϫ/Ϫ mice rescues the Th2 response in a model of asthma (14). Importantly, ITK and RLK are aberrantly overexpressed and activated in T-cell malignancies as well as inflammatory and autoimmune diseases, making these proteins particularly attractive therapeutic targets in these disorders (4,(15)(16)(17).…”