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. <br/> <br/>With our primary interest being the treatment of patients with rheumatoid arthritis, we sought non-covalent inhibitors of BTK.  In this presentation we will describe the development of our BTK inhibitors from our first generation through to our advanced leads, culminating in the highly optimised inhibitors GNE-504 and GNE-309.  These inhibitors are highly selective, have clean safety profiles and good pharmacokinetic properties.<br/> <br/>Additionally, 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 PLCγ2 (R665W).  In this presentation we will disclose the activity of these compounds against a range of BTK-mutant enzymes and cell-lines, including those with the C481S mutation, with their activity rationalized through structure based design.

Potent and selective pyridone BTK inhibitors with activity against mutant forms of BTK

249th National Meeting (2015)

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