A covalent BTK inhibitor
Branebrutinib is a covalent inhibitor of Bruton’s tyrosine kinase (BTK; IC50 = 0.1 nM).1 It is greater than 5,000-fold selective for BTK over a panel of 240 kinases but does inhibit the additional Tec family kinases Tec, BMX, and TMX (IC50s = 0.9, 1.5, and 5 nM, respectively). Branebrutinib inhibits calcium flux in Ramos B cells induced by B cell receptor (BCR) stimulation (IC50 = 7.2 nM), as well as BCR stimulation-induced proliferation of, and CD86 surface expression in, peripheral B cells (IC50s = 0.04 and 0.3 nM, respectively). It inhibits TNF-α production in human peripheral blood mononuclear cells (PMBCs) induced by Fcγ receptor stimulation (IC50 = 0.3 nM). Branebrutinib (0.5 mg/kg) is completely protective against bone destruction in a mouse model of collagen-induced arthritis. It also reduces proteinuria and glomerular IgG immune complex deposition and increases survival in an NZB/W lupus-prone mouse model.
1.Watterson, S.H., Liu, Q., Bertrand, M.B., et al.Discovery of branebrutinib (BMS-986195): A strategy for identifying a highly potent and selective covalent inhibitor providing rapid in vivo inactivation of Bruton's tyrosine kinase (BTK)J. Med. Chem.62(7)3228-3250(2019)
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