Delgocitinib (JTE-052)
(Synonyms: 迪高替尼,JTE-052) 目录号 : GC31660
Delgocitinib (JTE-052) (JTE-052) 是一种特异性 JAK 抑制剂，对 JAK1、JAK2、JAK3 和 Tyk2 的 IC50 分别为 2.8、2.6、13 和 58 nM。
Cas No.:1263774-59-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
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Cell experiment: |
in vitro experiments, Delgocitinib is dissolved in dimethyl sulfoxide (DMSO) and diluted with the buffer used in each experiment.--> For determination of IL-2-induced T cell proliferation, human T cells are precultured with 10 μg/mL PHA-M for 3 days and plated in 96-well plates at 1.0×104 cells/well in the presence or absence of various concentrations of Delgocitinib. Following preincubation with Delgocitinib for 30 min at 37°C, the cells are stimulated by adding 20 ng/mL recombinant human IL-2 to each well and incubated for 3 days at 37°C under 5 % CO2. After completion of the culture period, the cells are harvested with a 96-well harvester and counted in a scintillation counter[1]. |
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Animal experiment: |
in vivo experiments, Delgocitinib is suspended in 0.5 % (w/v) methyl cellulose solution.--> Lewis rats are used in this study. First, collagen-induced arthritis (CIA) is induced in rats. Lewis rats are immunized with 1 mL of the emulsion (1 mg of type II collagen) via ten intradermal injections on the back under anesthesia. The rats are then challenged with 0.2 mL of the emulsion injected into the base of the tail on day 8 under anesthesia. Delgocitinib is given orally once daily from day 1 to day 21 (preventive administration) or from day 15 to day 28 (therapeutic administration). After arthritis induction, the hind paw volume is measured by a water displacement method using a plethysmometer. On day 22 or day 29, the rats are euthanized, and their hind paws are excised and X-rayed or processed for histological evaluation[1]. |
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References: [1]. Tanimoto A, et al. Pharmacological properties of JTE-052: a novel potent JAK inhibitor that suppresses various inflammatory responses in vitro and in vivo. Inflamm Res. 2015 Jan;64(1):41-51. |
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Delgocitinib is a novel and specific JAK inhibitor with IC50s of 2.8, 2.6, 13 and 58 nM for JAK1, JAK2, JAK3 and Tyk2, respectively.
In the enzymatic assays, Delgocitinib potently inhibits all of the JAK subtypes with IC50 values of 2.8±0.6, 2.6±0.2, 13±0 and 58±9 nM for JAK1, JAK2, JAK3 and Tyk2, respectively. Lineweaver-Burk plots show that the inhibition mode of Delgocitinib toward all JAKs is competitive with ATP with Ki values of 2.1±0.3, 1.7±0.0, 5.5±0.3 and 14±1 nM for JAK1, JAK2, JAK3 and Tyk2, respectively. In these cell-based cytokine signaling assays, Delgocitinib inhibits the phosphorylation of Stat proteins induced by IL-2, IL-6, IL-23, GM-CSF, and IFN-α with IC50 values of 40±9, 33±14, 84±11, 304±22 and 18±3 nM, respectively. Delgocitinib also inhibits IL-2-induced proliferation of T cells in a concentration-dependent manner (IC50=8.9±3.6 nM), and its potency is similar to that of tofacitinib (IC50=16 nM)[1].
Delgocitinib decreases the IFN-γ production, but the potency of the 1-h prior administration is higher than that of the 6-h prior administration (ED50=0.24 versus 1.3 mg/kg). In the administration from day 1, Delgocitinib prevents the development of hind paw swelling and histological changes of inflammatory cell infiltration and synovial cell hyperplasia. Delgocitinib inhibits radiographic and histological changes of bone destruction and cartilage destruction. In the administration from day 15, Delgocitinib decreases the paw swelling in a dose-dependent manner. In addition, Delgocitinib ameliorates the inflammatory cell infiltration, synovial cell hyperplasia, and cartilage/bone destructions in the histological and radiographic examinations at the end of the study[1].
[1]. Tanimoto A, et al. Pharmacological properties of JTE-052: a novel potent JAK inhibitor that suppresses various inflammatory responses in vitro and in vivo. Inflamm Res. 2015 Jan;64(1):41-51.
| Cas No. | 1263774-59-9 | SDF | |
| 别名 | 迪高替尼,JTE-052 | ||
| Canonical SMILES | O=C(N(C[C@@H]1C)[C@]21CN(C3=C(C=CN4)C4=NC=N3)CC2)CC#N | ||
| 分子式 | C16H18N6O | 分子量 | 310.35 |
| 溶解度 | DMSO : ≥ 58 mg/mL (186.89 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.2222 mL | 16.1108 mL | 32.2217 mL |
| 5 mM | 0.6444 mL | 3.2222 mL | 6.4443 mL |
| 10 mM | 0.3222 mL | 1.6111 mL | 3.2222 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
JAK inhibitors in the treatment of atopic dermatitis
Atopic dermatitis (AD) is a chronic inflammatory skin disorder associated with heterogenous presentation and often immense patient burden. Safe, targeted treatment options are currently limited. This focused review of the published literature, including clinical trial results, case reports, and abstracts, as well as presentations from scientific meetings and data from industry press releases, describes the use of topical and systemic Janus kinase (JAK) inhibitors in the treatment of AD. New topical JAK inhibitors include ruxolitinib (JAK1/2) and delgocitinib (pan-JAK). Ruxolitinib cream met all primary and secondary endpoints in phase 3 clinical trials for mild-to-moderate AD with minimal treatment-emergent adverse events. Delgocitinib ointment was recently approved in Japan for pediatric and adult AD. Oral JAK inhibitors include baricitinib (JAK1/2), abrocitinib (JAK1-selective), and upadacitinib (JAK1-selective). All 3 met primary and secondary endpoints across numerous trials for moderate-to-severe AD. Treatment-emergent adverse events were mainly mild to moderate and included acne, nausea, headache, upper respiratory tract infection, and to a lesser degree, herpes infection and selected laboratory abnormalities. JAK inhibitors hold great promise as the next generation of targeted AD therapy. While their outstanding efficacy is balanced by a favorable safety profile in clinical trials, real-world data are needed to better understand long-term safety, durability, and treatment success.
Innovation in the treatment of atopic dermatitis: Emerging topical and oral Janus kinase inhibitors
Atopic dermatitis (AD) is characterized by chronic, eczematous, severe pruritic skin lesions. The knowledge on the pathogenesis of AD is driving the development of new drugs. From the research results, it has been revealed that Th2 cell-mediated immunity, skin barrier dysfunction, and pruritus cause a vicious cycle of AD. On the other hand, the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway are one of the essential signaling pathways in various inflammatory diseases including AD. In particular, TSLP, IL-4, IL-13 and IL-22 occupy an important position for Th2 cell-mediated immune reaction. Moreover, experimentally pan-JAK inhibitor suppress the STAT3 activation and improved the skin barrier function. Furthermore TSLP, IL-4, IL-13 and IL-31 contribute a lot to chronic pruritus of AD, and transmitted via JAK-STAT pathway. Therefore, JAK inhibitors are promising candidates for the treatment of severe AD. Here we review clinical trials of topical dergocitinib; a pan-JAK inhibitor, ruxolitinib; a JAK1 and JAK2 inhibitor, and tofacitinib; a JAK1, JAK2, and JAK3 inhibitor and oral baricitinib; a JAK1 and JAK2 inhibitor, abrocitinib and upadacitinib; JAK1 inhibitor. Significant improvements in the symptoms were obtained by each drug with low frequency of adverse events. In particular, oral JAK inhibitors have the ability to improve the pruritus and skin symptoms quickly. Therefore, the emergence of these topical and oral JAK inhibitors would be regarded as an innovation in the treatment of atopic dermatitis.
A Comprehensive Overview of Globally Approved JAK Inhibitors
Janus kinase (JAK) is a family of cytoplasmic non-receptor tyrosine kinases that includes four members, namely JAK1, JAK2, JAK3, and TYK2. The JAKs transduce cytokine signaling through the JAK-STAT pathway, which regulates the transcription of several genes involved in inflammatory, immune, and cancer conditions. Targeting the JAK family kinases with small-molecule inhibitors has proved to be effective in the treatment of different types of diseases. In the current review, eleven of the JAK inhibitors that received approval for clinical use have been discussed. These drugs are abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, and upadacitinib. The aim of the current review was to provide an integrated overview of the chemical and pharmacological data of the globally approved JAK inhibitors. The synthetic routes of the eleven drugs were described. In addition, their inhibitory activities against different kinases and their pharmacological uses have also been explained. Moreover, their crystal structures with different kinases were summarized, with a primary focus on their binding modes and interactions. The proposed metabolic pathways and metabolites of these drugs were also illustrated. To sum up, the data in the current review could help in the design of new JAK inhibitors with potential therapeutic benefits in inflammatory and autoimmune diseases.
The evolving atopic dermatitis management landscape
Introduction: Atopic dermatitis is a common dermatologic condition that affects millions of people worldwide, and a standardized approach to treatment was published by the American Academy of Dermatology (AAD) in 2013-14. Since 2014, new FDA-approved treatment options such as dupilumab and crisaborole have changed the landscape of AD management, and future therapies such as JAK inhibitors and anti-interleukin 13 and 31 antibodies appear effective, emphasizing the need for a comprehensive review to give clinicians an updated toolbox to aid in pharmacologic management.
Areas covered: In this review, the authors explore the updated efficacy and safety data on established therapeutic options for AD including topical corticosteroids, topical calcineurin inhibitors, cyclosporine, azathioprine, methotrexate, and mycophenolate mofetil. In addition, the authors also explore trial data and studies on dupilumab, crisaborole, omalizumab, tofacitinib, ruxolinitib, abrocitinib, baricitinib, upadacitinib, delgocitinib, nemoliuzumab, and tralokinumab.
Expert opinion: The AAD guidelines must be updated in the future to include several new treatment modalities that have revolutionized the pharmacologic management of patients with AD, including dupilumab and crisaborole. The future of AD treatment is also extremely bright, as JAK inhibitors and Il-13/31 antibodies have shown convincing results in the improvement of AD patients' lives in various trials and studies that have been examined in this paper.
Janus kinase inhibitors for the therapy of atopic dermatitis
The JAK-STAT pathway is involved in the signaling of multiple cytokines driving cutaneous inflammation in atopic dermatitis (AD). Janus kinase (JAK) inhibitors target individual receptor-associated kinases, thereby preventing the mediation of inflammatory signals. Several JAK inhibitors with varying mechanism of action, potency, and safety represent potential therapeutic options for AD in both topical and systemic application. The JAK1/2 selective JAK inhibitor baricitinib was the first substance from this class of drugs approved by the EMA for the systemic oral treatment of AD. The clinical development program of the JAK1 selective inhibitors upadacitinib and abrocitinib is finalized with positive results for AD. The PAN-JAK inhibitor delgocitinib was the first substance being approved for the treatment of AD (in Japan). This review article covers the rising data on investigational and approved JAK inhibitors in the context of the treatment of AD.