Tyk2-IN-4 (BMS-986165)

BMS 986165 is an allosteric inhibitor of tyrosine kinase 2 (TYK2; IC₅₀ = 0.2 nM for the recombinant TYK2 pseudokinase domain).¹ It is selective for TYK2 over a panel of 249 protein and lipid kinases at 1 ?M but does inhibit the JAK1 pseudokinase domain and bone morphogenetic protein receptor type II (BMPR2; IC₅₀s = 1 and 193 nM, respectively). BMS 986165 inhibits IFN-α-induced phosphorylation of STAT1, -2, -3, and -5 in primary human peripheral blood mononuclear cells (PBMCs; IC₅₀s = 1-6 nM). It also inhibits IL-12-induced production of IFN-γ in human PBMCs (IC₅₀ = 11 nM) and IL-12-induced phosphorylation of STAT4 in NK-92 cells (IC₅₀ = 5 nM). BMS 986165 (1 and 10 mg/kg) reduces IL-12 and IL-18-induced production of IFN-γ in mice. It inhibits IFN-regulated expression of IFIT3, IFIT1, and MX1, genes encoding innate antiviral response proteins, and reduces tubulointerstitial and glomerular nephritis in female NZB/W lupus-prone mice. BMS 986165 also inhibits anti-CD40 antibody-induced colitis and systemic wasting in mice.

1.Burke, J.R., Cheng, L., Gillooly, K.M., et al.Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudokinase domainSci. Transl. Med.11(502)eaaw1736(2019)