J Med Chem. 2019 Oct 24;62(20):8953-8972. doi: 10.1021/acs.jmedchem.9b00443. Epub 2019 Jul 17.
As a member of the Janus (JAK) family of nonreceptor tyrosine kinases, TYK2 plays an important role in mediating the signaling of pro-inflammatory cytokines including IL-12, IL-23, and type 1 interferons. The nicotinamide , identified by a SPA-based high-throughput screen targeting the TYK2 pseudokinase domain, potently inhibits IL-23 and IFNα signaling in cellular assays. The described work details the optimization of this poorly selective hit () to potent and selective molecules such as and . The discoveries described herein were critical to the eventual identification of the clinical TYK2 JH2 inhibitor (see following report in this issue). Compound provided robust inhibition in a mouse IL-12-induced IFNγ pharmacodynamic model as well as efficacy in an IL-23 and IL-12-dependent mouse colitis model. These results demonstrate the ability of TYK2 JH2 domain binders to provide a highly selective alternative to conventional TYK2 orthosteric inhibitors.
作为非受体酪氨酸激酶家族的 Janus（JAK）成员之一，TYK2 在介导包括白细胞介素-12（IL-12）、白细胞介素-23（IL-23）和 I 型干扰素在内的促炎细胞因子的信号转导中发挥着重要作用。通过针对 TYK2 假激酶结构域的 SPA 为基础的高通量筛选鉴定的烟酰胺，在细胞测定中能够强有力地抑制 IL-23 和 IFNα信号转导。所描述的工作详细说明了对这个选择性较差的化合物（）进行优化，得到了强效和选择性的分子，如和。本文所描述的发现对于最终鉴定出临床 TYK2 JH2 抑制剂（见本期该主题的后续报告）至关重要。化合物在小鼠白细胞介素-12 诱导的 IFNγ 药效学模型中提供了强大的抑制作用，并且在白细胞介素-23 和白细胞介素-12 依赖性小鼠结肠炎模型中具有疗效。这些结果表明，TYK2 JH2 结构域结合物具有提供一种高度选择性的替代传统 TYK2 变构抑制剂的能力。
