JAK inhibitors: Is specificity at all relevant?
JAK inhibitors: Is specificity at all relevant?
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JAK 抑制剂：特异性是否相关？
DOI：
10.1016/j.semarthrit.2023.152327
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发表时间：
2024
影响因子：
5
通讯作者：
Gadina,Massimo
中科院分区：
文献类型：
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作者：
Gadina,Massimo
背景细胞因子是影响宿主防御和维持免疫稳态的可溶性因子。细胞因子产生的改变会导致免疫反应功能失调和免疫相关疾病。细胞因子与特定受体结合并触发各种细胞内信号级联反应，靶向细胞因子和/或其受体可有效治疗炎症性疾病。目的I型和II型细胞因子受体激活四种Janus激酶(JAK)，即JAK1、JAK2、JAK3和TYK2，这些酶的靶向导致了现在称为JAK抑制剂或JAKinibs的成功药物的开发。结果JAKinibs可分为三类“几代人。”第一代 JAKinib 是一种以正位方式发挥作用的分子，可抑制多种 JAK 并干扰许多因子的生物活性。本着减少副作用的理念，第二代 JAKinib 仍是正位 ATP 竞争对手，已开发出对一种或两种 JAK 的更高选择性。第三代 JAKinibs 利用了我们对 JAK 结构域的结构和功能的更多了解，并且是变构抑制剂，因为它们与假激酶结构域中的特定残基结合。这些第三代 JAKInb 确实似乎拥有更好的安全性。值得注意的是，抑制特定组织中的细胞因子活性可能比选择性酶阻滞更重要，因此，局部、吸入或不可吸收的 JAKinibs 也在开发中。结论虽然 JAKinibs 大约十年前进入临床舞台，但我们对这些药物及其相对于其活性和安全性的选择性的了解仍然不完整。因此，需要更多的研究来更好地利用此类药物。
BackgroundCytokines are soluble factors that affect host defense and maintain immune homeostasis. Altered cytokine production leads to a dysfunctional immune responses and immune-related diseases. Cytokines bind to specific receptors and trigger various intracellular signaling cascades and targeting cytokines and/or their receptors has been effective in treating inflammatory diseases.ObjectivesType I and II cytokine receptors activate four Janus kinases (JAKs), namely JAK1, JAK2, JAK3 and TYK2 and targeting of these enzymes resulted in the development of successful drugs now referred as JAK inhibitors or JAKinibs.ResultsJAKinibs can be divided in three “generations.” First-generation JAKinibs, molecules acting in an orthosteric manner, inhibit multiple JAKs and interfere with the biologic activity of many factors. With the idea of reducing side effects, second-generation JAKinibs, still orthosteric ATP competitors, have been developed with increased selectivity towards one or two JAKs. Third-generation JAKinibs have exploited our increased understanding of the structure and function of JAK domains and are allosteric inhibitors as they bind to specific residues in the pseudokinase domain. These third generation JAKInb indeed seems to possess a better safety profile. Notably, inhibition of cytokine activity in specific tissues could be more important than selective enzymatic blockade and for this reason, topical, inhaled, or as a non-absorbable JAKinibs are also being developed.ConclusionsWhile JAKinibs entered the clinical arena about ten years ago, our understanding of these drugs and their selectivity relative to their activity and safety is still incomplete. More research is therefore needed to achieve better usage of these class of drugs.