Bruton’s tyrosine kinase (BTK), a key member of the B-cell receptor (BCR) signalling pathway and the first Tec family tyrosine kinase identified as a dual-function regulator of apoptosis, promotes radiation-induced apoptosis but inhibits Fas-activated apoptosis in B-cells. BTK is a cytoplasmic, non-receptor tyrosine kinase (nRTK) that transmits signals via a variety of cell-surface molecules and is expressed by all cells of the haematopoietic lineage except T, NK, and plasma cells. In 1952, American paediatrician Ogdon Bruton discovered X-linked agammaglobulinemia (XLA), an inherited disease characterized by the absence of antibodies, resulting in recurrent bacterial infections and sepsis early in childhood. In 1993, the gene underlying XLA was identified as agammaglobulinemia tyrosine kinase (ATK) and B-cell progenitor kinase (BPK). This gene was named BTK by Ogden Bruton. Studies have shown that BTK not only signals B-cell receptor (BCR) responses for antigen engagement but also stimulates CD40, is an oral, covalent, irreversible BTK inhibitor that exhibits high selectivity, prolonged pharmacodynamics, and potency in overcoming endogenous ATP competition by binding to Cys481 in the ATP-binding domain of BTK. Ibrutinib was first launched in the U.S. in 2013 for the treatment of MCL, and it was further used as a monotherapy for the treatment of CLL in 2014.
is a potent inhibitor of BTK and a third-generation, irreversible epidermal growth factor receptor (EGFR)-mutation-selective tyrosine kinase inhibitor. According to its molecular structure, olmutinib possesses a thieno-[3,2-d]-pyrimidine core and a typical terminal acrylamide, which serves as a Michael acceptor that covalently binds to Cys481 located in the BTK hinge segment.
is an orally available, potent, selective and covalent BTK inhibitor with an IC50 below 0.5nM. Spebrutinib was originally developed by Avila Therapeutics and was acquired by Celgene in March 2012.
RN-486 is a novel BTK inhibitor distinct from previous BTK inhibitors such as PCI-32765, CGI-1746 and GDC-0834. In contrast to the irreversible, covalently binding PCI-32765 and RN486 and the two previous reversible BTK inhibitors, CGI-1746 and GDC-0834, RN-486 can block the signalling pathway of BCR, as demonstrated by a marked inhibition of the phosphorylation of both BTK and PLC2 in B cells.
Liang, C., Tian, D., Ren, X., Ding, S., Jia, M., Xin, M., & Thareja, S. (2018). The development of Bruton's tyrosine kinase (BTK) inhibitors from 2012 to 2017: A mini-review. European journal of medicinal chemistry.
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