BMS-986142 is a potent and highly selective reversible BTK inhibitor (IC50: 0.5 nM).

TEC:10 nM (cell free), ITK:15 nM (cell free), BMX:32 nM (cell free), TXK:28 nM (cell free), BTK:0.5 nM (cell free), BLK:23 nM (cell free)

Against a panel of 384 kinases, BMS-986142 is highly selective, with only five other kinases (Tec, ITK, BLK, Txk, BMX) inhibited with <100-fold selectivity for BTK. Four of these kinases are Tec family kinases, of which BTK is a member, and only Tec (IC50: 10 nM) is inhibited with <30-fold selectivity compared with BTK. BMS-986142 does not inhibit CD40L-induced expression of CD86 or CD69 on peripheral blood B cells (IC50>10,000 nM for both). When Ramos B cells are treated with anti-IgM to activate BCR, BMS-986142 inhibits BTK-dependent calcium flux (IC50: 9 nM) [2].

BMS-986142 administration at doses of 4, 10, and 30 mg/kg produces dose-dependent decreases in clinically evident disease by 26%, 43%, and 79%, respectively. Notably, at a 4 mg/kg dose, BMS-986142, when used in conjunction with MTX, enhances clinical scores by achieving a 54% inhibition, compared to a 19% inhibition with MTX alone. Further, this co-administration at 4 mg/kg leads to a 53% reduction in inflammation and bone resorption, significantly more effective than the 24% and 10% reductions observed with each drug individually. Additionally, serum anti-collagen II IgG levels are notably reduced with 10 and 30 mg/kg doses of BMS-986142. The compound also demonstrates efficacy in delayed treatment protocols, showing dose-dependent improvements in clinical scores even when administration begins on day 21, with 2, 4, and 25 mg/kg doses resulting in clinical score reductions of 17%, 37%, and 67%, respectively, by study's end [2].

Male DBA/1 mice are injected subcutaneously at the base of the tail with bovine type II collagen (200 μg) admixed. The mice are boosted 21 days later in the same manner. For preventative administration, PO QD dosing is immediately started with BMS-986142 in EtOH: TPGS: PEG300 (5:5:90); for therapeutic administration, the start of dosing is delayed until the booster immunization on day 21. For BMS-986142 plus MTX preventative studies, mice receive vehicle; BMS-986142 at 4, 10, or 30 mg/kg; BMS-986142 at 4 mg/kg plus MTX 0.25 mg/kg; or MTX at 0.25 mg/kg daily. For BMS-986142 plus etanercept therapeutic studies, mice receive vehicle daily; BMS-986142 at 2, 4, or 25 mg/kg daily; BMS-986142 at 2 or 4 mg/kg daily plus etanercept at 15 mg/kg IP twice weekly (BIW); or etanercept at 15 mg/kg IP BIW. For BMS-986142 plus murine cytotoxic T lymphocyte-associated protein 4 immunoglobulins (CTLA-4-Ig) preventative studies, mice receive vehicle daily; BMS-986142 at 10 or 30 mg/kg daily; murine CTLA-4-Ig at 0.05 or 0.2 mg/kg IP BIW; or BMS-986142 at 10 mg/kg daily plus murine CTLA-4-Ig at 0.05 or 0.2 mg/kg IP BIW. Dosing proceeds from day 0 through study completion (36 days).