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(Synonyms: SHR0302) 目录号 : GC39802

SHR0302 是一种有效的具有口服活性的 JAK 抑制剂,尤其是 JAK1 的抑制剂。SHR0302 对 JAK1 的选择性是 JAK2 的 10 倍以上,是 JAK3 的 77 倍,是 Tyk2 的 420 倍。SHR0302 抑制 JAK1-STAT3 磷酸化并诱导肝星状细胞凋亡 (apoptosis)。SHR0302 具有抗增殖和抗炎作用。

SHR0302 Chemical Structure

Cas No.:1445987-21-2

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产品描述

SHR0302 is a potent and orally active all members of the JAK family inhibitor, particularly JAK1. The selectivity of SHR0302 for JAK1 is >10-fold for JAK2, 77-fold for JAK3, 420-fold for Tyk2. SHR0302 inhibits JAK1-STAT3 phosphorylation and induces the apoptosis of hepatic stellate cells. SHR0302 has anti-proliferative and anti-inflammatory effects[1][2].

[1]. Huaxun Wu, et al. JAK1-STAT3 Blockade by JAK Inhibitor SHR0302 Attenuates Inflammatory Responses of Adjuvant-Induced Arthritis Rats and Decreases Th17 and Total B Cells. Joint Bone Spine. 2016 Oct;83(5):525-32. [2]. Yuan-Jing Gu, et al. Targeted Blockade of JAK/STAT3 Signaling Inhibits Proliferation, Migration and Collagen Production as Well as Inducing the Apoptosis of Hepatic Stellate Cells. Int J Mol Med. 2016 Sep;38(3):903-11.

Chemical Properties

Cas No. 1445987-21-2 SDF
别名 SHR0302
Canonical SMILES O=C(N1C[C@@]2([H])[C@@](C[C@H](N(C)C3=C4C(NC=C4)=NC=N3)C2)([H])C1)NC5=NC(OC)=NS5
分子式 C18H22N8O2S 分子量 414.48
溶解度 DMSO: 31.25 mg/mL (75.40 mM) 储存条件 Store at -20°C
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Research Update

Efficacy and Safety of SHR0302, a Highly Selective Janus Kinase 1 Inhibitor, in Patients with Moderate to Severe Atopic Dermatitis: A Phase II Randomized Clinical Trial

Am J Clin Dermatol 2021 Nov;22(6):877-889.PMID:34374027DOI:10.1007/s40257-021-00627-2.

Background: Atopic dermatitis is a chronic, inflammatory condition causing a substantial burden to patients and caregivers. SHR0302 is an oral, highly selective, Janus kinase 1 inhibitor under investigation for inflammatory skin diseases. Objective: The aim of this study was to investigate the efficacy and safety of SHR0302 in Chinese patients with moderate to severe atopic dermatitis. Design and setting: A randomized, double-blind, placebo-controlled, multicenter, phase II trial was conducted in China between October 2019 and August 2020. Participants: Patients (n = 105) aged 18-75 years with moderate to severe dermatitis and nonresponsive or intolerant to topical or conventional systemic treatments were included. Interventions: Patients were randomly assigned in a ratio of 1:1:1 to receive SHR0302 4 mg once daily, SHR0302 8 mg once daily, or placebo for 12 weeks. Main outcome measures: The primary efficacy endpoint was the proportion of patients achieving Investigator's Global Assessment (IGA) response (IGA of 0 [clear] or 1 [almost clear] with improvement of ≥2 grades) at week 12. Secondary efficacy assessments included Eczema Area and Severity Index (EASI) and pruritus Numerical Rating Scale (NRS) scores. Results: At week 12, IGA response was achieved in nine patients (25.7%; 90% confidence interval [CI] 13.6-37.9%; p = 0.022) in the SHR0302 4 mg group, 19 patients (54.3%; 90% CI 40.4-68.1%; p < 0.001) in the SHR0302 8 mg group, and two patients (5.7%; 90% CI 0.0-12.2%) in the placebo group. EASI75 was achieved in 51.4% (p = 0.013), 74.3% (p < 0.001), and 22.9% of patients in the SHR0302 4 mg, SHR0302 8 mg, and placebo groups, respectively, while an NRS ≥3-point improvement occurred in 65.7% (p < 0.001), 74.3% (p < 0.001), and 22.9% of patients, respectively. Treatment-emergent adverse events were reported in 60.0%, 68.6%, and 51.4% of patients in the SHR0302 4 mg, SHR0302 8 mg, and placebo groups, respectively. The adverse events were mild in most cases. Three serious adverse events were reported, all being worsening of atopic dermatitis. No serious infection was reported. Conclusions and relevance: Oral SHR0302 was effective and well tolerated in Chinese adult patients with moderate to severe atopic dermatitis. Trial registration: ClinicalTrials.gov identifier: NCT04162899; URL: https://clinicaltrials.gov/ . Date first registered: 14 November 2019.

Quantification of SHR0302 in human plasma by UPLC-MS/MS and application to a pharmacokinetic study

Biomed Chromatogr 2022 Nov;36(11):e5474.PMID:35916260DOI:10.1002/bmc.5474.

SHR0302, as a novel Janus kinase (JAK) inhibitor 1, is used for treatment of rheumatoid arthritis (RA) in humans. A novel and sensitive ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) has been developed and validated for determining the concentration of SHR0302 in human plasma. A precipitation deproteinization method was used for plasma pretreatment with methanol. Detection was carried out on an Agilent 1,260 UPLC coupled with a Triple Quad 4000 mass spectrometer operated in positive multiple reaction monitoring mode, and the analytes were separated on a Synergi Polar-RP C18 (50 × 2.0 mm, 4 μm, Phenomenex) analytical column with gradient elution of 0.1% formic acid, and 2 mmol/l ammonium acetate in water and 0.1% formic acid and 2 mmol/l ammonium acetate in methanol, The selected ion transitions were m/z 415.2 → 258.2 and m/z 398.2 → 258.2 for SHR0302 and SHR143181 (internal standard), respectively. A full validation, including selectivity, linearity, carryover, precision, accuracy, recovery, matrix effect, dilution integrity and stability, was carried out in human plasma. It was successfully applied to a pharmacokinetic study in Chinese healthy subjects after oral administration of SHR0302 tablet.

Association of Risk of Incident Venous Thromboembolism With Atopic Dermatitis and Treatment With Janus Kinase Inhibitors: A Systematic Review and Meta-analysis

JAMA Dermatol 2022 Nov 1;158(11):1254-1261.PMID:PMC9403856DOI:10.1001/jamadermatol.2022.3516.

Importance: The risk of venous thromboembolism (VTE) among patients with atopic dermatitis (AD), especially when receiving treatment with Janus kinase (JAK) inhibitors, is unclear. Objective: To determine the association of AD with incident VTE and evaluate the risk of incident VTE among patients with AD who were receiving treatment with JAK inhibitors. Data sources: The MEDLINE, Embase, Cochrane Library, and Web of Science databases were searched with no restrictions on language nor geographic locations from their respective inception to February 5, 2022. Study selection: Cohort studies examining the association of AD with incident VTE and randomized clinical trials (RCTs) reporting VTE events in participants with AD receiving JAK inhibitors were included. Around 0.7% of initially identified articles met the selection criteria. Data extraction and synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed. The risk of bias of included cohort studies and RCTs was assessed by the Newcastle-Ottawa Scale and the Cochrane Risk of Bias Tool 2, respectively. A random-effects model meta-analysis was conducted to calculate the pooled hazard ratio (HR) and risk difference for incident VTE. Main outcomes and measures: The HRs for incident VTE associated with AD and risk difference for incident VTE between participants with AD who were receiving treatment with JAK inhibitors and controls receiving placebo or dupilumab. Results: Two cohort studies and 15 RCTs with a total of 466 993 participants were included. The meta-analysis found no significant association of AD with incident VTE (HR, 0.95; 95% CI 0.62-1.45; incidence rate of VTE, 0.23 events/100 patient-years). Overall, 3 of 5722 patients with AD (0.05%) who were receiving treatment with JAK inhibitors experienced VTE compared with 1 of 3065 patients with AD (0.03%) receiving placebo or dupilumab (Mantel-Haenszel risk difference, 0; 95% CI, 0-0). The incidence rate of VTE was 0.15 and 0.12 events per 100 patient-years in participants with AD receiving JAK inhibitors and placebo, respectively. The findings were similar in 4 unique JAK inhibitors (abrocitinib, baricitinib, upadacitinib, and SHR0302). Conclusions and relevance: The results of this systematic review and meta-analysis suggest that the currently available evidence does not detect an increased risk of VTE associated with AD or treatment with JAK inhibitors. These findings may provide a reference for clinicians in prescribing JAK inhibitors for patients with AD.

Preventive and Therapeutic Effects of a Novel JAK Inhibitor SHR0302 in Acute Graft-Versus-Host Disease

Cell Transplant 2021 Jan-Dec;30:9636897211033778.PMID:34269100DOI:10.1177/09636897211033778.

Acute graft-versus-host disease (aGVHD) is one of the most common complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Janus kinase (JAK) inhibitors are considered as reliable and promising agents for patients with aGVHD. The prophylactic and therapeutic effects of SHR0302, a novel JAK inhibitor, were evaluated in aGVHD mouse models. The overall survival (OS), progression-free survival (PFS), bodyweight of mice, GVHD scores were observed and recorded. The bone marrow and spleen samples of diseased model mice or peripheral blood of patients were analyzed. SHR0302 could prevent and reverse aGVHD in mouse models with preserving graft-versus-tumor effect. Functionally, SHR0302 improved the OS and PFS, restored bodyweight, reduced GVHD scores, and reduced immune cells infiltrated in target tissues. SHR0302 treatment also enhanced the hematopoietic reconstruction compared to the control group. Mechanistically, our results suggested that SHR0302 could inhibit the activation of T cells and modulate the differentiation of helper T (Th) cells by reducing Th1 and increasing regulatory T (Treg) cells. In addition, SHR0302 decreased the expression of chemokine receptor CXCR3 on donor T cells and the secretion of cytokines or chemokines including interleukin (IL)-6, interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), CXCL10, etc. thereby destroying the IFN-γ/CXCR3/CXCL10 axis which promotes the progression of GVHD. Besides, SHR0302 decreased the phosphorylation of JAK and its downstream STATs, AKT and ERK1/2, which ultimately regulated the activation, proliferation, and differentiation of lymphocytes. Experiments on primary cells from aGVHD patients also confirmed the results. In summary, our results indicated that JAK inhibitor SHR0302 might be used as a novel agent for patients with aGVHD.

A Phase I Study to Evaluate the Safety and Pharmacokinetics of SHR0302 Base Ointment in Healthy Adult Volunteers

Skin Pharmacol Physiol 2022 Dec 29.PMID:36580897DOI:10.1159/000528739.

Introduction: SHR0302 is a highly selective JAK1 inhibitor. This study aims to investigate the safety, tolerability, and pharmacokinetics of single- and multiple-dose topical skin application of SHR0302 base ointment in healthy adult subjects. Methods: This phase I clinical trial (registration number: CTR20192188) consisted of two parts. Part 1 was a single-dose ascending study with four dose levels in 32 healthy Australian adults (eight subjects in each dose group). All Australian subjects were randomized 3:1 to a single-dose topical skin application of SHR0302 base ointment or placebo. The dose escalated from 1% SHR0302 base ointment on 3% of body surface area (BSA) to 2% SHR0302 base ointment on 20% of BSA. Part 2 combined single- and multiple-dose-ascension studies with two dose levels in 20 healthy Chinese adults (10 subjects in each dose group). All Chinese subjects were randomized 4:1 to a combination of single and multiple doses for consecutive 10 days of topical application of 1% SHR0302 base ointment on 20% BSA or 2% SHR0302 base ointment on 20% BSA. The safety and pharmacokinetics of the SHR0302 base ointment were evaluated. Results: The incidence of treatment-emergent adverse events (TEAEs) in both parts was comparable between the SHR0302 base ointment group and the vehicle group (Part 1:33.3% vs. 37.5%; Part 2: 56.3% vs. 75.0%). All TEAEs were transient, recovered, and equally well-tolerated in the two racial groups. The overall absorption of the SHR0302 base ointment was slow after topical application, with Tmax>10 h. After a single dose of the SHR0302 base ointment, drug exposure in healthy Australian and Chinese subjects increased non-linearly with the increase in the administration area and drug content. Drug exposure increased in a less-than-dose-proportional manner within the dose range tested. Due to differences in the clinical practice of topical application, the Tmax of the drug in Australian subjects was earlier than in Chinese subjects, but the overall extent of absorption seemed comparable in Australian and Chinese subjects (with comparable AUC0-t). Conclusion: The SHR0302 base ointment (either single or multiple doses) was well tolerated and safe, with no racial disparity.