Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Clinical Research Center for Cancer Immunotherapy, Xiangya Hospital, Central South University, Changsha, Hunan, China.
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Southern Medical University Affiliated Fengxian Hospital, Shanghai, China.
Biomed Pharmacother. 2023 Nov;167:115611. doi: 10.1016/j.biopha.2023.115611. Epub 2023 Sep 29.
Tyrosine kinase 2 (TYK2) as a member of Janus kinase (JAK) family, mainly mediates the signaling of type I interferons (IFN), interleukin-12 (IL-12) and interleukin-23 (IL-23), which has become an attractive target for treatment of immune and inflammatory diseases. However, the development of selective TYK2 inhibitors is challenging due to the high homology of the catalytic kinase domain among the JAK family members. Here, we report a novel and potent allosteric inhibitor, WD-890, which binds to the pseudokinase domain of TYK2 with high selectivity and inhibits its function. We accomplished a series of preclinical studies to demonstrate the therapeutic efficacy of WD-890 in four animal models: systemic lupus erythematosus (SLE), psoriasis, psoriatic arthritis (PsA), and inflammatory bowel disease (IBD). The pharmacokinetic and toxicology results further indicate that WD-890 has favorable absorption, distribution, metabolism, and excretion (ADME) properties and tolerable toxicity. In conclusion, our study shows that WD-890 could be a promising oral TYK2 inhibitor for future treatment of autoimmune diseases.
酪氨酸激酶 2（TYK2）作为 Janus 激酶（JAK）家族的一员，主要介导 I 型干扰素（IFN）、白细胞介素-12（IL-12）和白细胞介素-23（IL-23）的信号转导，已成为治疗免疫和炎症性疾病的有吸引力的靶点。然而，由于 JAK 家族成员的催化激酶结构域高度同源，选择性 TYK2 抑制剂的开发具有挑战性。在这里，我们报告了一种新型有效的变构抑制剂 WD-890，它与 TYK2 的假激酶结构域具有高选择性结合，并抑制其功能。我们完成了一系列临床前研究，以证明 WD-890 在四种动物模型中的治疗效果：系统性红斑狼疮（SLE）、银屑病、银屑病关节炎（PsA）和炎症性肠病（IBD）。药代动力学和毒理学结果进一步表明，WD-890 具有良好的吸收、分布、代谢和排泄（ADME）特性和可耐受的毒性。总之，我们的研究表明，WD-890 可能成为一种有前途的口服 TYK2 抑制剂，用于未来治疗自身免疫性疾病。
