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JH-X-119-01 Sale

目录号 : GC63925

JH-X-119-01 is a highly potent and selective covalent inhibitor of IRAK1 with IC50 of 9 nM.

JH-X-119-01 Chemical Structure

Cas No.:2227368-54-7

规格 价格 库存 购买数量
5 mg
¥1,620.00
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10 mg
¥2,430.00
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25 mg
¥4,410.00
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50 mg
¥6,570.00
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100 mg
¥8,910.00
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产品描述

JH-X-119-01 is a highly potent and selective covalent inhibitor of IRAK1 with IC50 of 9 nM.

JH-X-119-01 is a highly efficient and selective covalent inhibitor of interleukin 1 (IL-1) receptor-associated kinase (IRAK) 1 and irreversibly labels IRAK1 at C302, showing moderate cell killing effects with EC50s ranging from 0.59 to 9.72 μM in a panel of WM cells, DLBCL cells, and lymphoma cells.[1]

[1] John M Hatcher, et al. ACS Med Chem Lett. 2020 Oct 9;11(11):2238-2243.

Chemical Properties

Cas No. 2227368-54-7 SDF Download SDF
分子式 C25H20N6O3 分子量 452.46
溶解度 DMSO : 250 mg/mL (552.54 mM; Need ultrasonic) 储存条件 Store at -20°C
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1 mM 2.2101 mL 11.0507 mL 22.1014 mL
5 mM 0.442 mL 2.2101 mL 4.4203 mL
10 mM 0.221 mL 1.1051 mL 2.2101 mL
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Research Update

Selective inhibition of interleukin-1 receptor-associated kinase 1 ameliorates lipopolysaccharide-induced sepsis in mice

Int Immunopharmacol 2020 Aug;85:106597.PMID:32422509DOI:10.1016/j.intimp.2020.106597.

Interleukin-1 receptor-associated kinases (IRAKs), particularly IRAK1 and IRAK4, are important in transducing signal from Toll-like receptor 4. We interrogated if a selective inhibition of IRAK1 could alleviate lipopolysaccharide (LPS)-induced sepsis. In this study, we tested the impact of a novel selective IRAK1 inhibitor JH-X-119-01 on LPS-induced sepsis in mice. Survival at day 5 was 13.3% in control group where septic mice were treated by vehicle, while the values were 37.5% (p = 0.046, vs. control) and 56.3% (p = 0.003, vs. control) for 5 mg/kg and 10 mg/kg Jh-X-119-01-treated mice. JH-X-119-01 alleviated lung injury and reduced production of TNFα and IFNγ in peritoneal macrophages. JH-X-119-01 decreased phosphorylation of NF-κB and mRNA levels of IL-6 and TNFα in LPS-treated macrophages in vitro. JH-X-119-01 selectively inhibited IRAK1 phosphorylation comparing with a non-selective IRAK1/4 inhibitor which simultaneously inhibited phosphorylation of IRAK1 and IRAK4. Both JH-X-119-01 and IRAK1/4 inhibitor increased survival of septic mice, but Jh-X-119-01-treated mice had higher blood CD11b+ cell counts than IRAK1/4 inhibitor-treated ones [24 h: (1.18 ± 0.26) × 106/ml vs. (0.79 ± 0.20) × 106/ml, p = 0.001; 48 h: (1.00 ± 0.30) × 106/ml vs. (0.67 ± 0.23) × 106/ml, p = 0.042]. IRAK1/4 inhibitor induced more apoptosis of macrophages than JH-X-119-01 did in vitro. IRAK1/4 inhibitor decreased protein levels of anti-apoptotic BCL-2 and MCL-1 in RAW 264.7 and THP-1 cells, an effect not seen in Jh-X-119-01-treated cells. In conclusion, JH-X-119-01 selectively inhibited activation of IRAK1 and protected mice from LPS-induced sepsis. JH-X-119-01 showed less toxicity on macrophages comparing with a non-selective IRAK1/4 inhibitor.

Inhibition of IL-1 Receptor-Associated Kinase 1 Decreases Murine Acute Graft-versus-Host Disease While Preserving the Graft-versus-Lymphoma Effect

Transplant Cell Ther 2022 Mar;28(3):134.e1-134.e10.PMID:34896653DOI:10.1016/j.jtct.2021.12.001.

Activation of antigen-presenting cells (APCs) is crucial in initiating inflammation and alloreaction during acute graft-versus-host disease (aGVHD), a common life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). IL-1 receptor-associated kinase 1 (IRAK1) regulates the activation of APCs in inflammatory settings, and inhibition of IRAK1 might decrease APC activation and aGVHD. This study was conducted to explore the impact of IRAK1 inhibition on APC activation and aGVHD in mice. We administered a selective IRAK1 inhibitor, JH-X-119-01, to recipient mice undergoing allo-HCT or co-challenged by A20 lymphoma cells. We assessed aGVHD and the graft-versus-lymphoma (GVL) effect. T cell and APC activations were analyzed as well. JH-X-119-01 was associated with increased survival and decreased aGVHD of recipients. JH-X-119-01 decreased the proportions of Th1 cells and Tc1 cells in the aGVHD model and in the in vitro mixed lymphocyte reaction. The IRAK1 inhibitor reduced production of TNFα and IFNγ in macrophages of recipient mice. In in vitro cultured bone marrow dendritic cells (BMDCs), JH-X-119-01 decreased productions of inflammatory cytokines, reduced expression levels of CD80 and CD86, and decreased protein levels of antiapoptotic Bcl2 and phosphorylated NF-κB p65. RNA-seq analysis showed that JH-X-119-01 had an impact on several pathophysiologic processes of BMDCs, including reduction of GVHD-related genes and regulation of helper T cell differentiation. Importantly, IRAK1 inhibition did not impair cytotoxic function of T cells or the allo-HCT-related GVL effect against A20 lymphoma cells. In addition, the IRAK1 inhibitor did not retard recovery of hematopoietic cells in blood or bone marrow. Our findings show that selective IRAK1 inhibition ameliorates murine aGVHD but preserves the GVL effect. Our findings may have implications for the use of an IRAK1 inhibitor in allo-HCT.

Discovery of a Selective, Covalent IRAK1 Inhibitor with Antiproliferative Activity in MYD88 Mutated B-Cell Lymphoma

ACS Med Chem Lett 2020 Oct 9;11(11):2238-2243.PMID:33214835DOI:10.1021/acsmedchemlett.0c00378.

Interleukin 1 (IL-1) receptor-associated kinases (IRAKs) are serine/threonine kinases that play critical roles in initiating the innate immune response against foreign pathogens. Additionally, dysregulation of IRAK1 signaling plays a role in neoplastic disorders. For example, IRAK1 was shown to be important for survival and proliferation in many B-cell lymphomas, including Waldenström's macroglobulinemia (WM) and ABC subtype Diffused Large B-cell Lymphoma (DLBCL) cells. Here, we report the discovery of a highly potent and selective covalent inhibitor of IRAK1, JH-X-119-01. Intact protein MS labeling studies confirmed that JH-X-119-01 irreversibly labels IRAK1 at C302. This compound exhibited cytotoxic activity at single digit micromolar concentrations in a panel of WM, DLBCL, and lymphoma cell lines expressing MYD88. Cotreatment of JH-X-119-01 with the BTK inhibitor ibrutinib resulted in synergistic killing effects in these systems. Taken together, JH-X-119-01 represents a highly selective probe of IRAK1 for further development.