Selectivity Profile of the Tyrosine Kinase 2 Inhibitor Deucravacitinib Compared with Janus Kinase 1/2/3 Inhibitors.
Selectivity Profile of the Tyrosine Kinase 2 Inhibitor Deucravacitinib Compared with Janus Kinase 1/2/3 Inhibitors.
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DOI：
10.1007/s13555-021-00596-8
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发表时间：
2021-10
影响因子：
3.4
通讯作者：
Throup J
中科院分区：
文献类型：
--
作者：
Chimalakonda A;Burke J;Cheng L;Catlett I;Tagen M;Zhao Q;Patel A;Shen J;Girgis IG;Banerjee S;Throup J
Deucravacitinib是一种新型的口服选择性酪氨酸激酶2（TYK 2）信号传导抑制剂，通过与酶的调节结构域而不是催化结构域结合，通过变构机制发挥作用。这种独特的结合为TYK 2提供了相对于密切相关的Janus激酶（JAK）1/2/3的高功能选择性。Deucravacitinib在II期和III期银屑病试验中有效，未观察到指示JAK 1/2/3抑制的临床或实验室参数。该分析比较了deucravacitinib与JAK 1/2/3抑制剂在治疗暴露下的激酶特异性。在体外全血测定中测量经由JAK 1/3、JAK 2/2和TYK 2/JAK 2二聚体的信号传导。测定deucravacitinib和JAK 1/2/3抑制剂托法替尼、upadacitinib和baricitinib在这些试验中提供半数最大抑制（IC 50）的浓度。使用II/III期试验中评价的剂量，将新得出的全血IC 50值与可用的药代动力学曲线作图。评价了模拟的平均每日抑制和浓度超过IC 50的持续时间。在临床相关暴露量下，预计稳态deucravacitinib血浆浓度在约9-18小时内高于TYK 2 IC 50。deucravacitinib的最大血浆浓度（Cmax）比JAK 1/3 IC 50低8- 17倍，比JAK 2/2 IC 50低> 48-> 102倍。deucravacitinib的模拟每日平均TYK 2抑制范围为50%-69%。模拟表明，稳态时托法替尼、upadacitinib和baricitinib在治疗浓度下表现出不同程度的JAK 1/3（每日平均抑制率，70-94%）和JAK 2/2（23%-67%）抑制，Cmax值比其TYK 2 IC 50水平低17- 33倍。在临床相关剂量和暴露量下，deucravacitinib表现出对TYK 2而非JAK 1/2/3的高度选择性抑制。托法替尼、upadacitinib和baricitinib可抑制JAK 1/2/3，但不抑制TYK 2。这些结果表明，与JAK 1/2/3抑制剂相比，deucravacitinib是一种独特的激酶抑制剂。牛皮癣是一种常见的慢性炎症性皮肤病，损害患者的身体健康，情绪健康，工作表现和整体生活质量。银屑病和相关疾病如银屑病关节炎是由免疫系统异常引起的。使用或探索各种药物来治疗这些病症，包括Janus激酶（JAK）抑制剂;然而，JAK抑制剂与一系列副作用相关，例如血细胞、胆固醇和甘油三酯水平的异常变化，以及肝脏和肾脏功能障碍。Deucravacitinib是一种正在开发的新型口服药物，可阻断参与银屑病发病机制的关键分子酪氨酸激酶2（TYK 2）。该分析比较了deucravacitinib与批准的JAK 1/2/3抑制剂（托法替尼、upadacitinib和baricitinib）在全血测定中对TYK 2和JAK 1/2/3的选择性，使用每种药物的治疗剂量。作者报告称，deucravacitinib可抑制TYK 2，对JAK 1/2/3的抑制极小或无抑制。相反，托法替尼、upadacitinib和baricitinib在不同程度上抑制JAK 1、JAK 2和/或JAK 3，但不抑制TYK 2。这些结果表明，与JAK 1/2/3抑制剂相比，deucravacitinib是一种独特的药物。该分析的结果与最近在中重度斑块状银屑病患者中完成的两项III期试验（POETYK PSO-1和PSO-2）以及一项银屑病II期试验的结果一致，其中deucravacitinib有效且耐受性良好，未观察到提示JAK 1/2/3抑制的临床或实验室异常。
Deucravacitinib, a novel, oral, selective inhibitor of tyrosine kinase 2 (TYK2) signaling, acts via an allosteric mechanism by binding to the enzyme’s regulatory domain instead of the catalytic domain. This unique binding provides high functional selectivity for TYK2 versus the closely related Janus kinases (JAKs) 1/2/3. Deucravacitinib was efficacious in phase 2 and 3 psoriasis trials, without clinical or laboratory parameters indicative of JAK 1/2/3 inhibition being observed. This analysis compared the kinase specificities of deucravacitinib versus JAK 1/2/3 inhibitors at therapeutic exposures. Signaling via JAK 1/3, JAK 2/2, and TYK2/JAK 2 dimers was measured in in vitro whole blood assays. Concentrations providing half-maximal inhibition (IC50) in these assays were determined for deucravacitinib and the JAK 1/2/3 inhibitors tofacitinib, upadacitinib, and baricitinib. Newly derived whole blood IC50 values were plotted against available pharmacokinetic profiles using doses evaluated in phase 2/3 trials. Simulated average daily inhibition and durations over which concentrations exceeded IC50 were evaluated. At clinically relevant exposures, projected steady-state deucravacitinib plasma concentrations were higher than TYK2 IC50 for approximately 9–18 h. Maximal plasma concentrations (Cmax) of deucravacitinib were 8- to 17-fold lower than JAK 1/3 IC50 and > 48- to > 102-fold lower than JAK 2/2 IC50. Simulated daily average TYK2 inhibition by deucravacitinib ranged from 50% to 69%. Simulations indicated that tofacitinib, upadacitinib, and baricitinib at steady state exhibited varying degrees of JAK 1/3 (daily average inhibition, 70–94%) and JAK 2/2 (23%–67%) inhibition at therapeutic concentrations, with Cmax values 17- to 33-fold lower than their TYK2 IC50 levels. At clinically relevant doses and exposures, deucravacitinib demonstrates highly selective inhibition of TYK2 and not JAK 1/2/3. Tofacitinib, upadacitinib, and baricitinib variably inhibit JAK 1/2/3 but not TYK2. These results indicate that deucravacitinib is a distinct class of kinase inhibitor compared with JAK 1/2/3 inhibitors. Psoriasis is a common, chronic inflammatory skin condition that impairs patients’ physical health, emotional well-being, work performance, and overall quality of life. Psoriasis and related conditions such as psoriatic arthritis are caused by abnormalities in the immune system. Various drugs are used or explored to treat these conditions, including Janus kinase (JAK) inhibitors; however, JAK inhibitors are associated with a range of side effects such as abnormal changes in blood cell, cholesterol, and triglyceride levels, as well as liver and kidney dysfunction. Deucravacitinib is a new oral drug in development that blocks a key molecule involved in the pathogenesis of psoriasis known as tyrosine kinase 2 (TYK2). This analysis compared the selectivity of deucravacitinib versus approved JAK 1/2/3 inhibitors (tofacitinib, upadacitinib, and baricitinib) for TYK2 and JAK 1/2/3 in whole blood assays, using therapeutic doses of each drug. The authors reported that deucravacitinib inhibits TYK2 with minimal or no inhibition of JAK 1/2/3. In contrast, tofacitinib, upadacitinib, and baricitinib inhibit JAK 1, JAK 2, and/or JAK 3 to various degrees but do not inhibit TYK2. These results demonstrate that deucravacitinib is a distinct class of drug compared with the JAK 1/2/3 inhibitors. The results of this analysis are consistent with those of two recently completed phase 3 trials in patients with moderate-to-severe plaque psoriasis (POETYK PSO-1 and PSO-2), as well as a phase 2 trial in psoriasis, in which deucravacitinib was efficacious and well tolerated, without clinical or laboratory abnormalities suggestive of JAK 1/2/3 inhibition being observed.
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