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Ruxolitinib (INCB018424) Sale

(Synonyms: 芦可替尼; INCB18424) 目录号 : GC14191

Ruxolitinib (INCB018424)能够抑制Janus相关激酶(JAKs)JAK1和JAK2, IC50分别为 3.3 nM 和 2.8 nM。

Ruxolitinib (INCB018424) Chemical Structure

Cas No.:941678-49-5

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实验参考方法

Cell experiment [1]:

Cell lines

HMC1 cells

Preparation method

Cells were seeded in a 96-well plate at 2×105 cells in 200 μL culture medium per condition. Subsequently, the cells were incubated for 30 minutes with ruxolitinib before stimulating them with 1 μmol/L of A23187 or 5 μmol/L of substance P. TNF-α levels in the supernatant were measured after 6 hours of stimulation, and MCP-1 and IL-6 levels were measured after 24 hours of stimulation.

Reaction Conditions

500nM-50μM;30min

Applications

Ruxolitinib significantly inhibited the production of IL-6, TNF-α and MCP-1 as induced by A23817 and substance P in HMC1 cells.

Animal experiment [2]:

Animal models

Male C57BL/6 mice

Preparation method

Mice were randomly assigned to three groups with 5 mice in each group as follows: (1) Sham-operated mice with vehicle (Sham); (2) Unilateral ureteral obstruction (UUO) mice with vehicle (UUO); (3) UUO mice treated with Ruxolitinib (UUO+RUX). To establish UUO model, mice were given general anesthesia by intraperitoneal injection of pentobarbital (50mg/kg body weight). The left ureter was exposed via a left flank incision, ligated with 4-0 silk at two points, and cut between the 2 ligation points. The Sham-operated group had no ligation.

For in vivo experiments, Ruxolitinib was dissolved in PEG300/dextrose 5%l in a ratio of 1:3 (PEG/dex) and administered to mice by oral gavage at a dosage of 30 mg/kg twice daily for 14 days immediately after UUO or Sham-operation. The Sham and UUO group received PEG/dex alone as vehicle. Thel mice were sacrificed at days 14 after surgery.

Dosage form

30 mg/kg; p.o.; twice a day 14 days

Applications

Ruxolitinib treatment alleviated renal damage in UUO mice.

References:

[1]. Hermans MAW, Schrijver B, et,al. The JAK1/JAK2- inhibitor ruxolitinib inhibits mast cell degranulation and cytokine release. Clin Exp Allergy. 2018 Nov;48(11):1412-1420. doi: 10.1111/cea.13217. Epub 2018 Aug 3. PMID: 29939445.

[2]. Bai Y, Wang W, et,al. Ruxolitinib Alleviates Renal Interstitial Fibrosis in UUO Mice. Int J Biol Sci. 2020 Jan 1;16(2):194-203. doi: 10.7150/ijbs.39024. PMID: 31929748; PMCID: PMC6949153.

产品描述

Ruxolitinib (INCB018424), as an inhibitor, inhibits Janus-associated kinases (JAKs)JAK1 and JAK2 with IC50 values of 3.3 nM and 2.8 nM, respectively. Ruxolitinib mediates several cytokine and growth factor signaling important for hematopoietic and immune function[1-3].

Ruxolitinib (INCB018424) (500nM-50μM;30min) significantly inhibited the production of IL-6, TNF-α and MCP-1 as induced by A23817 and substance P in HMC1 cells[4]. Ruxolitinib(0-400nM; 3days) reduced the level of cytokine release in CAR-T cells[5].

Ruxolitinib (INCB018424) (30 mg/kg; p.o.; twice a day 14 days) treatment alleviated renal damage in UUO mice[6]. Ruxolitinib(twice daily by oral gavage; 2 weeks) treatment improves viability and splenomegaly in a JAK2V617F-driven model of malignant disease[3]. Treatment of Fancc-/- mice with ruxolitinib(45 mg/kg; i.p; 5 days/week) decreased anemia, enhanced granulocytosis, delayed clonal progression and prolonged survival during repeated emergency granulopoiesis episodes[7].

References:

[1]. Becker H, Engelhardt M, et,al. Ruxolitinib. Recent Results Cancer Res. 2014;201:249-57. doi: 10.1007/978-3-642-54490-3_16. PMID: 24756798.

[2]. Ajayi S, Becker H, et,al. Ruxolitinib. Recent Results Cancer Res. 2018;212:119-132. doi: 10.1007/978-3-319-91439-8_6. PMID: 30069628.

[3]. Quintás-Cardama A, Vaddi K, et,al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood. 2010 Apr 15;115(15):3109-17. doi: 10.1182/blood-2009-04-214957. Epub 2010 Feb 3. PMID: 20130243; PMCID: PMC3953826.

[4]. Hermans MAW, Schrijver B, et,al. The JAK1/JAK2- inhibitor ruxolitinib inhibits mast cell degranulation and cytokine release. Clin Exp Allergy. 2018 Nov;48(11):1412-1420. doi: 10.1111/cea.13217. Epub 2018 Aug 3. PMID: 29939445.

[5]. Xu N, Yang XF, et,al. Ruxolitinib reduces severe CRS response by suspending CAR-T cell function instead of damaging CAR-T cells. Biochem Biophys Res Commun. 2022 Mar 5;595:54-61. doi: 10.1016/j.bbrc.2022.01.070. Epub 2022 Jan 20. PMID: 35101664.

[6]. Bai Y, Wang W, et,al. Ruxolitinib Alleviates Renal Interstitial Fibrosis in UUO Mice. Int J Biol Sci. 2020 Jan 1;16(2):194-203. doi: 10.7150/ijbs.39024. PMID: 31929748; PMCID: PMC6949153.

[7]. Hasan S, Hu L, et,al. Ruxolitinib ameliorates progressive anemia and improves survival during episodes of emergency granulopoiesis in Fanconi C-/- mice. Exp Hematol. 2022 May;109:55-67.e2. doi: 10.1016/j.exphem.2022.03.001. Epub 2022 Mar 9. PMID: 35278531; PMCID: PMC9064927.

Ruxolitinib (INCB018424)作为一种抑制剂,能够抑制Janus相关激酶(JAKs)JAK1和JAK2, IC50 分别为 3.3 nM 和 2.8 nM,Ruxolitinib介导对造血和免疫功能重要的若干细胞因子和生长因子信号[1-3]

Ruxolitinib (INCB018424) (500nM-50μM;30min)显著抑制A23817和substance P诱导的HMC1细胞中IL-6、TNF-α和MCP-1的产生[4]。Ruxolitinib (0-400nM; 3days)降低CAR-T细胞中细胞因子的释放水平[5]

Ruxolitinib (INCB018424)治疗(30 mg/kg; p.o.; twice a day 14 days)可减轻UUO小鼠肾损害[6]。Ruxolitinib治疗(twice daily by oral gavage; 2 weeks)改善JAK2V617F-driven的恶性疾病小鼠的生存能力和脾肿大情况[3]。用Ruxolitinib (45 mg/kg; i.p; 5 days/week)治疗Fancc-/-小鼠可减少贫血,增强粒细胞功能,延迟克隆进展,延长反复紧急粒细胞生成发作期间的生存期[7]

Chemical Properties

Cas No. 941678-49-5 SDF
别名 芦可替尼; INCB18424
化学名 (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile
Canonical SMILES C1CCC(C1)C(CC#N)N2C=C(C=N2)C3=C4C=CNC4=NC=N3
分子式 C17H18N6 分子量 306.37
溶解度 ≥ 15.32mg/mL in DMSO 储存条件 Store at -20°C
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溶解性数据

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1 mM 3.264 mL 16.3201 mL 32.6403 mL
5 mM 0.6528 mL 3.264 mL 6.5281 mL
10 mM 0.3264 mL 1.632 mL 3.264 mL
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Research Update

Ruxolitinib

Ruxolitinib, formerly known as INCB018424 or INC424, is a potent and selective oral inhibitor of Janus kinase (JAK) 1 and JAK2. Ruxolitinib has been approved for the treatment of myelofibrosis (MF) by the US Food and Drug Administration (FDA) in 2011 and by the European Medicines Agency (EMA) in 2012, followed by the approval for the treatment of hydroxyurea (HU)-resistant or -intolerant polycythemia vera (PV) in 2014. Both MF and PV are myeloproliferative neoplasms (MPNs) which are characterized by the aberrant activation of the JAK-STAT pathway. Clinically, MF features bone marrow fibrosis, splenomegaly, abnormal blood counts, and poor quality-of-life through associated symptoms. PV is characterized by the overproduction of primarily red blood cells (RBC), risk of thrombotic complications, and development of secondary MF. Ruxolitinib treatment results in a meaningful reduction in spleen size and symptom burden in the majority of MF patients and may also have a favorable effect on survival. In PV, ruxolitinib effectively controls the hematocrit and reduces splenomegaly. Since recently, ruxolitinib is also under investigation for the treatment of graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Toxicities of ruxolitinib include myelosuppression, which results in dose-limiting thrombocytopenia and anemia, and viral reactivations. The metabolization of ruxolitinib through CYP3A4 needs to be considered particularly if co-administered with potent CYP3A4 inhibitors. Several further JAK inhibitors are currently under investigation for MPNs or other immuno-inflammatory diseases.

Management of myelofibrosis after ruxolitinib failure

Myelofibrosis is a BCR-ABL1-negative myeloproliferative neoplasm characterized by anemia, progressive splenomegaly, extramedullary hematopoiesis, bone marrow fibrosis, constitutional symptoms, leukemic progression, and shortened survival. Constitutive activation of the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway, and other cellular pathways downstream, leads to myeloproliferation, proinflammatory cytokine expression, and bone marrow remodeling. Transplant is the only curative option for myelofibrosis, but high rates of morbidity and mortality limit eligibility. Several prognostic models have been developed to facilitate treatment decisions. Until the recent approval of fedratinib, a JAK2 inhibitor, ruxolitinib was the only available JAK inhibitor for treatment of intermediate- or high-risk myelofibrosis. Ruxolitinib reduces splenomegaly to some degree in almost all treated patients; however, many patients cannot tolerate ruxolitinib due to dose-dependent drug-related cytopenias, and even patients with a good initial response often develop resistance to ruxolitinib after 2-3 years of therapy. Currently, there is no consensus definition of ruxolitinib failure. Until fedratinib approval, strategies to overcome ruxolitinib resistance or intolerance were mainly different approaches to continued ruxolitinib therapy, including dosing modifications and ruxolitinib rechallenge. Fedratinib and two other JAK2 inhibitors in later stages of clinical development, pacritinib and momelotinib, have been shown to induce clinical responses and improve symptoms in patients previously treated with ruxolitinib. Fedratinib induces robust spleen responses, and pacritinib and momelotinib may have preferential activity in patients with severe cytopenias. Reviewed here are strategies to ameliorate ruxolitinib resistance or intolerance, and outcomes of clinical trials in patients with myelofibrosis receiving second-line JAK inhibitors after ruxolitinib treatment.

Ruxolitinib Alleviates Renal Interstitial Fibrosis in UUO Mice

Ruxolitinib is a selective inhibitor of Jak1/2. Downstream signaling pathways of Jak, such as Stat3 and Akt/mTOR, are overactivated and contribute to renal interstitial fibrosis. Therefore, we explored the effect of Ruxolitinib on this pathological process. Unilateral ureteral obstruction (UUO) models and TGF-β1-treated fibroblasts and renal tubular epithelial cells were adopted in this study. Ruxolitinib was administered to UUO mice and TGF-β1-treated cells. Kidneys from UUO mice with Ruxolitinib treatment displayed less tubular injuries compared with those without Ruxolitinib treatment. Ruxolitinib treatment suppressed fibroblast activation and extracellular matrix (ECM) production in UUO kidneys and TGF-β1-treated fibroblasts. Ruxolitinib treatment also blocked epithelial-mesenchymal transition (EMT) in UUO kidneys and TGF-β 1-treated renal tubular epithelial cells. Moreover, Ruxolitinib treatment alleviated UUO-induced inflammation, oxidative stress and apoptosis. Mechanistically, Ruxolitinib treatment attenuated activation of both Stat3 and Akt/mTOR/Yap pathways. In conclusion, Ruxolitinib treatment can ameliorate UUO-induced renal interstitial fibrosis, suggesting that Ruxolitinib may be potentially used to treat fibrotic kidney disease.

A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis

Background: Ruxolitinib, a selective inhibitor of Janus kinase (JAK) 1 and 2, has clinically significant activity in myelofibrosis.
Methods: In this double-blind trial, we randomly assigned patients with intermediate-2 or high-risk myelofibrosis to twice-daily oral ruxolitinib (155 patients) or placebo (154 patients). The primary end point was the proportion of patients with a reduction in spleen volume of 35% or more at 24 weeks, assessed by means of magnetic resonance imaging. Secondary end points included the durability of response, changes in symptom burden (assessed by the total symptom score), and overall survival.
Results: The primary end point was reached in 41.9% of patients in the ruxolitinib group as compared with 0.7% in the placebo group (P<0.001). A reduction in spleen volume was maintained in patients who received ruxolitinib; 67.0% of the patients with a response had the response for 48 weeks or more. There was an improvement of 50% or more in the total symptom score at 24 weeks in 45.9% of patients who received ruxolitinib as compared with 5.3% of patients who received placebo (P<0.001). Thirteen deaths occurred in the ruxolitinib group as compared with 24 deaths in the placebo group (hazard ratio, 0.50; 95% confidence interval, 0.25 to 0.98; P=0.04). The rate of discontinuation of the study drug because of adverse events was 11.0% in the ruxolitinib group and 10.6% in the placebo group. Among patients who received ruxolitinib, anemia and thrombocytopenia were the most common adverse events, but they rarely led to discontinuation of the drug (in one patient for each event). Two patients had transformation to acute myeloid leukemia; both were in the ruxolitinib group.
Conclusions: Ruxolitinib, as compared with placebo, provided significant clinical benefits in patients with myelofibrosis by reducing spleen size, ameliorating debilitating myelofibrosis-related symptoms, and improving overall survival. These benefits came at the cost of more frequent anemia and thrombocytopenia in the early part of the treatment period. (Funded by Incyte; COMFORT-I ClinicalTrials.gov number, NCT00952289.).

Updated recommendations on the use of ruxolitinib for the treatment of myelofibrosis

Objectives: Myelofibrosis is a rare bone marrow disorder associated with a high symptom burden, poor prognosis, and shortened survival. While allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for myelofibrosis, the only approved and reimbursed pharmacotherapy for non-HSCT candidates in Belgium is ruxolitinib.
Methods: These updated recommendations are based on a consensus reached during two meetings and provide guidance for ruxolitinib administration in myelofibrosis patients considering the particularities of Belgian reimbursement criteria.
Results and discussion: In Belgium, ruxolitinib is indicated and reimbursed for transplant-ineligible myelofibrosis patients from intermediate-2- and high-risk groups and from the intermediate-1-risk group with splenomegaly. Our recommendation is to also make ruxolitinib available in the pre-transplant setting for myelofibrosis patients with splenomegaly or heavy symptom burden. Before ruxolitinib initiation, complete blood cell counts are recommended, and the decision on the optimal dosage should be based on platelet count and clinical parameters. In anemic patients, we recommend starting doses of ruxolitinib of 10 mg twice daily for 12 weeks and we propose the use of erythropoiesis-stimulating agents in patients with endogenous erythropoietin levels ≤500 mU/mL. Increased vigilance for opportunistic infections and second primary malignancies is needed in ruxolitinib-treated myelofibrosis patients. Ruxolitinib treatment should be continued as long as there is clinical benefit (reduced splenomegaly or symptoms), and we recommend progressive dose tapering when stopping ruxolitinib.
Conclusion: Based on new data and clinical experience, the panel of experts discussed ruxolitinib treatment in Belgian myelofibrosis patients with a focus on dose optimization/monitoring, adverse events, and interruption/rechallenge management.