![]() BTK is a non-receptor protein-tyrosine kinase that belongs to the TEC family of kinases. The understanding of the B-cell receptor (BCR) signaling pathway led to the deciphering of the central role of Bruton’s tyrosine kinase (BTK) and the importance of its inhibition as an effective strategy for the treatment of B-cell malignancies ( Herman et al., 2011 Smith, 2017 Pal Singh et al., 2018 Lucas and Woyach, 2019). Conversely, cardiovascular AEs, like hypertension and various forms of heart disease, often persist.īTK, B-Lymphocyte Development and X-Linked Agammaglobulinemia Moreover, dermatological toxicities, diarrhoea, bleedings and invasive fungal infections often develop early after BTKi treatment initiation and subsequently subside. However, the binding pattern of BTKis to various additional kinases does not correlate with the common assumption that skin manifestations and diarrhoeas are off-target effects related to EGF receptor inhibition. Analysis of the reported AEs suggests that ibrutinib-associated atrial fibrillation is caused by binding to ERBB2/HER2 and ERBB4/HER4. Adverse effects (AEs) have predominantly implicated inhibition of other kinases with a BTKi-binding cysteine in their catalytic domain. However, an increasing number of trials instead addresses autoimmunity and inflammation in multiple sclerosis, rheumatoid arthritis, pemphigus and systemic lupus erythematosus with the use of either irreversibly binding inhibitors, e.g., evobrutinib and tolebrutinib, or reversibly binding inhibitors, like fenebrutinib. In most cases, these compounds have been used for the treatment of B-lymphocyte tumors. Next-generation inhibitors, acalabrutinib and zanubrutinib, are approved both in the United States and in Europe, and zanubrutinib also in China, while tirabrutinib is currently only registered in Japan. First-in-class was ibrutinib, an irreversible binder forming a covalent bond to a cysteine in the catalytic region of the kinase, for which we have identified 228 active trials listed at. The number of BTK inhibitors (BTKis) in the clinic has increased considerably and currently amounts to at least 22. The cytoplasmic protein-tyrosine kinase BTK plays an essential role for differentiation and survival of B-lineage cells and, hence, represents a suitable drug target. ![]() 3Centre for Rare Diseases, Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.2Departamento de Ciencias Básicas, Universidad Industrial de Santander, Bucaramanga, Colombia.1Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden. ![]() Yesid Estupiñán 1,2, Anna Berglöf 1, Rula Zain 1,3 and C. ![]()
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