JAK 抑制剂同时影响多种细胞因子途径，从而能够高效治疗癌症和免疫介导疾病等复杂疾病。然而，它们的广泛影响也带来了安全问题，这刺激了对选择性越来越高的 JAK 抑制剂的需求。 Deucravacitinib 是一种一流的 TYK2 变构抑制剂，代表了该领域的显着进步。 deucravacitinib 并非像经典 JAK1-3 抑制剂那样竞争激酶结构域催化位点，而是靶向 TYK2 的调节性假激酶结构域。它惊人地反映了进化保守的天然存在的 TYK2 变体 P1104A 的功能效应，已知该变体可以预防多种自身免疫性疾病，同时提供足够的 TYK2 介导的细胞因子信号传导以预防免疫缺陷。 deucravacitinib 前所未有的高功能选择性和功效安全性特征（最初在银屑病中得到证实），加上遗传支持，以及早期 SLE 临床试验中的有希望的结果，使得该抑制剂已经成熟，可以探索其他自身免疫性疾病，从而找到更好、安全和有效的治疗方法急需。版权所有 © 2023 作者。由 Elsevier B.V. 出版。保留所有权利。

JAK inhibitors impact multiple cytokine pathways simultaneously, enabling high efficacy in treating complex diseases such as cancers and immune-mediated disorders. However, their broad reach also poses safety concerns, which have fuelled a demand for increasingly selective JAK inhibitors. Deucravacitinib, a first-in-class allosteric TYK2 inhibitor, represents a remarkable advancement in the field. Rather than competing at kinase domain catalytic sites as classical JAK1-3 inhibitors, deucravacitinib targets the regulatory pseudokinase domain of TYK2. It strikingly mirrors the functional effect of an evolutionary conserved naturally occurring TYK2 variant, P1104A, known to protect against multiple autoimmune diseases yet provide sufficient TYK2-mediated cytokine signalling required to prevent immune deficiency. The unprecedentedly high functional selectivity and efficacy-safety profile of deucravacitinib, initially demonstrated in psoriasis, combined with genetic support, and promising outcomes in early SLE clinical trials make this inhibitor ripe for exploration in other autoimmune diseases for which better, safe, and efficacious treatments are urgently needed.Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.