BTK regulates downstream of multiple receptors including innate immune receptors, B-cell antigen, chemokine and growth factors. In B cells, BTK is located downstream of the BCR, which then phosphorylate phospholipase-Cγ2 (PLCγ2), leading to calcium mobilization and activation of the nuclear factor-κB (NF-κB) and mitogen-activated protein (MAP) kinase pathways. BTK plays important roles in a diverse range of cellular processes, such as cell proliferation, survival, differentiation, motility, angiogenesis, cytokine production, and antigen presentation.
BTK inhibitors function by interfering the process of B cell maturity, and modulate the innate immune activity. However, first-generation BTK inhibitor such as Ibrutinib has unwanted side effects, including bleeding, rash, diarrhea and atrial fibrillation which were thought to be mostly associated with its off-target effects on the EGFR, ITK and other Tec family proteins. Therefore, a potent, orally bioavailable BTK inhibitor with higher selectivity than Ibrutinib would have therapeutic potential with less side effects in the future.
Small molecules with BTK-inhibitory property have emerged as promising therapeutic agents for the treatment of hematological malignancies, including Chronic lymphocytic leukemia (CLL), Mantle cell lymphoma (MCL), Marginal zone lymphoma (MZL) as well Waldenstrom's macroglobulinemia (WM). Research into immuno-inflammatory diseases such as rheumatoid arthritis (RA), Multiple Sclerosis (MS) are ongoing.