molecules of the month


oral reversible selective BTK kinase inhibitor

related cmpds in dev. for inflamm. conditions

from rational design of prior crystallized leads

ACS Med. Chem. Lett., Sep. 22, 2020

Bristol Myers Squibb, Princeton, NJ

Structure of BMS-986143, a potent, reversible inhibitor of the Bruton's tyrosine kinase (BTK)
1 min read

BMS-986143 is a potent, reversible inhibitor of the Bruton’s tyrosine kinase (BTK), which has been successfully targeted by a number of irreversible drugs for oncology. The safety bar is much higher for inflammatory conditions, however, which led the BMS team to pursue reversible inhibitors. The two defined axial stereocenters of compounds like 986413 were introduced as a way to address earlier observed in vivo safety issues with a prior lead that had free rotation about both axes and could be more promiscuous. I found it surprising that these molecules are not only configurationally stable but also stable to metabolism and hydrolysis of the pyridopyrimidinedione heterocycle in vivo. Amazingly, the BMS team took a related molecule into clinical efficacy studies, the >200…

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