Bruton’s tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR)-mediated signaling.  BTK also plays a critical role in the downstream signaling pathways for the Fc-gamma receptor in monocytes, the Fc-epsilon receptor in granulocytes, and the RANK receptor in osteoclasts.  As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis.  This presentation will outline the evolution of our strategy to identify covalent inhibitors of BTK that have the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically.  With excellent in vivo efficacy and a very desirable tolerability profile, BMS-986195 has advanced into clinical studies.  The structure of BMS-986195 will be disclosed.

Discovery of BMS-986195: A strategy for identifying a highly potent and selective covalent inhibitor providing rapid inactivation of Bruton’s tyrosine kinase (BTK)

255th National Meeting (2018)

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