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 µM 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.

1.1: lithium bromide; N-ethyl-N,N-diisopropylamine / water; acetonitrile / 25 °C
2.1: zinc diacetate / water; isopropyl alcohol / 65 °C / Large scale
3.1: (R)-1-[(Sp)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine; palladium diacetate; 1,8-diazabicyclo[5.4.0]undec-7-ene; potassium carbonate / toluene; acetonitrile / 75 °C / Inert atmosphere; Large scale
4.1: 1-methyl-1H-imidazole / acetonitrile; 1-methyl-pyrrolidin-2-one / 65 °C / Large scale
4.2: 65 °C / Large scale

1.Current Patent Assignee: BRISTOL MYERS SQUIBB - WO2019/232138, 2019, A1. 
2.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 domain. Sci. Transl. Med. 11(502), eaaw1736 (2019).