Bruton's tyrosine kinase (BTK) plays a critical role in the development, differentiation and proliferation of B-lineage cells, making it an attractive target for the treatment of immunological disorders as well as B-cell lymphoma.  There have been significant efforts from the pharmaceutical community with the goal of identifying BTK inhibitors for the treatment of immune disorders.  Of these, the most advanced to date is Ibrutinib, which launched in 2013 for cancer indications.  It has been reported that some patients have acquired resistance to ibrutinib therapy, and these have been shown to have mutations in BTK (C481S) and its direct substrate PLC?2 (R665W).  Herein we disclose BTK inhibitors that are active against a range of BTK-mutant enzymes, including C481S.

Potent and selective pyridone BTK inhibitors with an induced fit binding mode and activity vs. mutant forms of BTK

248th National Meeting (2014)

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