WHI-P154

JAK/STAT通路抑制剂；抑制JAK3

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产品号 #73552_C

JAK/STAT通路抑制剂；抑制JAK3

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总览

WHI-P154 是Janus激酶3（JAK3）的抑制剂，对人和小鼠蛋白的IC₅₀值分别为28和128 μM（Sudbeck et al.）。据报道，它还表现出对其他激酶的显著抑制，包括nM范围内的表皮生长因子受体（EGFR）（Changelian et al.; Uckun et al.）。尚未观察到对JAK1或JAK2的显著抑制（Sudbeck et al.）。

分化
·促进小鼠神经元前体细胞分化为神经元和少突胶质细胞，但阻止星形胶质细胞分化（Kim et al.）。
·消除PDGF诱导的人神经祖细胞神经突生长增加（Richards et al.）。

免疫学
·抑制脂多糖（LPS）诱导的巨噬细胞和人上皮细胞中一氧化氮合酶的表达和一氧化氮的生成（Sareila et al.）。

癌症研究
·诱导人胶质母细胞瘤细胞系U373和U87的凋亡和细胞死亡。与EGF偶联时，可抑制小鼠异种移植模型中的肿瘤生长（Narla et al.）。

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Product Information Sheet

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WHI-P154

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73552

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English

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WHI-P154

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73552

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English

技术资料 (3)

Differential regulation of proliferation and differentiation in neural precursor cells by the Jak pathway. Kim YH et al. Stem cells (Dayton, Ohio) 2010

Abstract

Neuronal precursor cells (NPCs) are temporally regulated and have the ability to proliferate and differentiate into mature neurons, oligodendrocytes, and astrocytes in the presence of growth factors (GFs). In the present study, the role of the Jak pathway in brain development was investigated in NPCs derived from neurosphere cultures using Jak2 and Jak3 small interfering RNAs and specific inhibitors. Jak2 inhibition profoundly decreased NPC proliferation, preventing further differentiation into neurons and glial cells. However, Jak3 inhibition induced neuronal differentiation accompanied by neurite growth. This phenomenon was due to the Jak3 inhibition-mediated induction of neurogenin (Ngn)2 and NeuroD in NPCs. Jak3 inhibition induced NPCs to differentiate into scattered neurons and increased the expression of Tuj1, microtubule associated protein 2 (MAP2), Olig2, and neuroglial protein (NG)2, but decreased glial fibrillary acidic protein (GFAP) expression, with predominant neurogenesis/polydendrogenesis compared with astrogliogenesis. Therefore, Jak2 may be important for NPC proliferation and maintenance, whereas knocking-down of Jak3 signaling is essential for NPC differentiation into neurons and oligodendrocytes but does not lead to astrocyte differentiation. These results suggest that NPC proliferation and differentiation are differentially regulated by the Jak pathway.

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Janus kinase 3 inhibitor WHI-P154 in macrophages activated by bacterial endotoxin: differential effects on the expression of iNOS, COX-2 and TNF-alpha. Sareila O et al. International immunopharmacology 2008

Abstract

Bacterial endotoxin is a potent inducer of inflammatory response, including the induction of inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production, and the expression of cyclo-oxygenase (COX)-2 and tumor necrosis factor (TNF)-alpha in inflammatory cells. In the present study, we investigated the effects of pharmacological inhibition of Janus kinase (JAK) 3 on the production of these proinflammatory molecules in macrophages exposed to bacterial endotoxin (lipopolysaccharide; LPS). JAK3 inhibitors WHI-P154 (4-(3'-bromo-4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline) and its derivative WHI-P131 inhibited LPS-induced iNOS expression and NO production in a dose-dependent manner. WHI-P154 inhibited the activation of signal transducer and activator of transcription (STAT) 1 and the expression of iNOS mRNA but it had no effect on iNOS mRNA decay when determined by actinomycin D assay. The JAK3 inhibitor had no effect on COX-2 expression, and TNF-alpha production was slightly inhibited only at higher drug concentrations (30 microM). In addition, WHI-P154 inhibited iNOS expression and NO production also in human epithelial cells. Our results suggest that JAK3 inhibition modulates human and murine iNOS expression and NO production in response to inflammatory stimuli.

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The specificity of JAK3 kinase inhibitors. Changelian PS et al. Blood 2008

Abstract

PF-956980 is a selective inhibitor of JAK3, related in structure to CP-690550, a compound being evaluated in clinical trials for rheumatoid arthritis and prevention of allograft rejection. PF-956980 has been evaluated against a panel of 30 kinases, and found to have nanomolar potency against only JAK3. Cellular and whole blood activity of this compound parallels its potency and selectivity in enzyme assays. It was effective in vivo at inhibiting the delayed type hypersensivity reaction in mice. We compared 2 commercially available JAK3 inhibitors (WHI-P131 and WHI-P154) in the same panel of biochemical and cellular assays and found them to be neither potent nor selective for JAK3. Both were found to be nanomolar inhibitors of the EGF receptor family of kinases. As these compounds have been used in numerous publications in the transplant and autoimmune disease literature, their specificity should be considered when interpreting these results.

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