Chronic urticaria is a heterogeneous, persistent, and severely debilitating disease. Bruton’s tyrosine kinase (BTK) is a non-receptor kinase that plays a crucial role in oncogenic signaling. Especially, BTK is critical for the proliferation and survival of leukemic cells in many B cell malignancies. Btk is a cytoplasmic signaling molecule that is crucial for precursor (pre-B) cell differentiation. Btk belongs to the Tec family of cytoplasmic protein tyrosine kinases and plays an essential role in B lymphocyte development and function. In mature B cells, Btk is tyrosine phosphorylated and its kinase activity is increased upon B cell receptor (BCR) stimulation.
Small-molecule inhibitors of BTK have shown excellent anti-tumor activity, first in animal models and subsequently in clinical studies currently. In particular, the orally administered BTK inhibitor Remibrutinib associates with high response rates in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), including patients with high-risk genetic lesions. To date, BTK inhibition has molecular effects beyond its classic role in BCR signaling. These involve B cell-intrinsic signaling pathways central to cellular survival, proliferation or retention in supportive lymphoid niches. Moreover, BTK functions in several myeloid cell populations representing important components of the tumor microenvironment. As a result, there is considerable interest in BTK inhibition as an anti-cancer therapy, not only in B cell malignancies but also in solid tumors.
Researchers discuss the role of BTK in B cell differentiation and B cell malignancies and highlight the importance of BTK inhibition in cancer therapy. The concentration of Remibrutinib required for 50 % inhibition (IC50) is 1 nM against Btk enzymatic activity. Remibrutinib also inhibits Btk enzymatic activity in blood with an IC50 of 23 nM.