Next-generation Bruton’s Tyrosine Kinase (BTK) Inhibitors Potentially Targeting BTK C481S Mutation- Recent Developments and Perspectives

Bruton’s tyrosine kinase (BTK) plays a vital role in B-cell antigen receptor (BCR) signalling transduction pathway. Controlling BCR signalling by BTK inhibitors is a promising therapeutic approach for the treatment of inflammatory and autoimmune diseases. Since the approval of ibrutinib for the treatment of different haematological cancers in 2013, great efforts have been made to explore new BTK inhibitors. Despite the remarkable potency and efficacy of first and second generation irreversible BTK inhibitors against various lymphomas and leukaemia, there are also some clinical limitations, such as off-target toxicity and primary/acquired drug resistance. Acquired drug resistance due to the C481S mutation in BTK is the major challenging problem of irreversible inhibitors. After, the BTK C481S mutation, the irreversible covalent inhibitors cannot form covalent bond with BTK and drop activities. Hence, there is an urgent need to develop novel BTK inhibitors to overcome the mutation problem. In recent years, a few reversible BTK inhibitors have been developed and are under clinical evaluation stages. In addition, a few reversible BTK-PROTACs have been explored and under developments. A number of reversible non-covalent BTK inhibitors, including MK1026/ ARQ531, LOXO305, fenebrutinib are at different stages of clinical trials for autoimmune diseases. In this review, we summarized the discovery and development of nextgeneration BTK inhibitors, especially targeting BTK C481S mutation and their applications for the treatment of lymphomas and autoimmune diseases.