BMS-986142

In B cells stimulated through the B cell receptor (BCR), BMS-986142 potently inhibits signaling and functional end points, including calcium flux (IC50 = 9 nM), production of cytokines, proliferation, and surface expression of the costimulatory molecule CD86 (IC50 = 3−4 nM). In T cells, ITK-catalyzed phosphorylation of PLCγ1 stimulated through the T cell receptor (TCR) is at least 45-fold less potently inhibited by BMS-986142 than BTK-dependent signaling end points in B cells, as expected based on the 30-fold selectivity for BTK over ITK in the enzymatic assays^[2].

B-cell receptor (BCR)-stimulated phospholipase C (PLC)-γ2 phosphorylation in Ramos B cells: After 1 hour of pre-incubation of Ramos B cells in media containing 10% fetal bovine serum (FBS) with varying concentrations of BMS-986142 at 37°C, the cells are stimulated with AffiniPure F(ab’)2 fragment goat anti-human immunoglobulin (Ig)M at 50 μg/mL for exactly 2 minutes at 37°C, followed by addition of ice-cold phosphate-buffered saline for quenching. The cells are pelleted and lysed, and PLCγ2 levels are measured by immunoblot using rabbit anti-human phosphoY759-PLCγ2 and analyzed using the Odyssey Infrared Imaging System with normalization to an actin control to ensure consistent loading.

In multispecies pharmacokinetic studies, the absolute oral bioavailability of BMS-986142 is 93% in mice, 67% in rats, 33% in cynomolgus monkeys, and 100% in dogs. The total body plasma clearance of BMS-986142 is low in all species. The large steady-state volume of distribution observed is indicative of extravascular distribution, in spite of the high protein binding. However, brain penetration is very low in rats (<5% of plasma concentration). BMS-986142 blocks the increase in severe proteinuria in a female NZB/W lupus-prone mouse model in vivo. Treatment with BMS-986142 provides robust protection against tubulo-interstitial and glomerular nephritis, as well as inflammatory infiltration^[2].