Protein kinases, the largest family of human enzymes, encompass well over 500 proteins. Specifically, tyrosine kinases phosphorylate proteins on the phenolic moiety of tyrosine residues. The tyrosine kinase family includes members that control cell growth, migration, and differentiation. Abnormal kinase activity has been implicated in a variety of human diseases including cancers, autoimmune and inflammatory diseases.
Btk is a member of the Tec family of tyrosine kinases, and has been shown to be a critical regulator of early B-cell development and mature B-cell activation and survival (Khan et al. Immunity 1995 3:283; Ellmeier et al. J. Exp. Med. 2000 192:1611). B-cell signaling through the B-cell receptor (BCR) leads to a wide range of biological outputs, which in turn depend on the developmental stage of the B-cell. The magnitude and duration of BCR signals must be precisely regulated. Aberrant BCR-mediated signaling can cause deregulated B-cell activation and/or the formation of pathogenic auto-antibodies leading to multiple autoimmune and/or inflammatory diseases.
Evidence for a role for Btk in autoimmune and inflammatory diseases has also been provided by Btk-deficient mouse models. In preclinical murine models of systemic lupus erythematosus (SLE), Btk-deficient mice show marked amelioration of disease progression. In addition, Btk-deficient mice are resistant to collagen-induced arthritis (Jansson and Holmdahl Clin. Exp. Immunol. 1993 94:459). A selective Btk inhibitor has been demonstrated dose-dependent efficacy in a mouse arthritis model (Pan et al., Chem. Med Chem. 2007 2:58-61).
Btk is also expressed by cells other than B-cells that may be involved in disease processes. For example, Btk is expressed by mast cells and Btk-deficient bone marrow derived mast cells demonstrate impaired antigen induced degranulation (Iwaki et al. J. Biol. Chem. 2005 280:40261). This shows Btk could be useful to treat pathological mast cell responses such as allergy and asthma. Also monocytes from XLA patients, in which Btk activity is absent, show decreased TNFα production following stimulation (Horwood et al. J Exp Med 197:1603, 2003). Therefore, TNFα mediated inflammation could be inhibited by small molecule inhibitors of Btk. Also, Btk has been reported to play a role in apoptosis (Islam and Smith Immunol Rev 178:49, 2000) and thus Btk inhibitors would be useful for the treatment of certain B-cell lymphomas and leukemias (Feldhahn et al. J Exp Med 201:1837, 2005).
On Jun. 16, 2012, Biopharmaceutical Company Pharmacyclics announced 2 new phase Ib/II clinical experimental results (PCYC-1102 and PCYC-1108) by using Btk inhibitor Ibrutinib (PCI-32765) for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The experimental results indicated that 61 patients with relapsed/refractory and 31 untreated patients with CLL are highly active and well tolerated, in addition, during the test, none of the patients was discontinuous because of adverse events.
Obviously, the excellent clinical results of Ibrutinib show that highly selective small molecule Btk inhibitors will be the hot star in the field of global drug development.
USPTO Backgrounds
USPTO Backgrounds