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FMK

现货
Catalog No.
A3420
RSK抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 2,860.00
Ship with 10-15 days
10mg
¥ 3,360.00
Ship with 10-15 days
5mg
¥ 2,300.00
Ship with 10-15 days

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Background

FMK is a potent, highly specific and irreversible ribosomal s6 kinase (RSK) inhibitor with IC50 value of 15 nM.[1]
RSK is named for ribosomal protein s6, part of the translational machinery which are serine/threonine kinases and are activated by the MAPK/ERK pathway. There are two subfamilies of RSK, p90rsk, also known as MAPK-activated protein kinase-1 (MAPKAP-K1), and p70rsk, also known as S6-H1 Kinase or simply S6 Kinase.90 kDa ribosomal S6 kinases(p90rsk),the first substrates of ERK,is a ubiquitous and versatile mediator of ERK signal transduction which regulates protein synthesis by phosphorylation of polyribosomal proteins and glycogen synthase kinase-3 and phosphorylates the Ras GTP/GDP-exchange factor, leading to feedback inhibition of the Ras-ERK pathway.[2]
FMK is an irreversible inhibitor that covalently modifies the C-terminal kinase domain of RSK. It therefore prevents the activation of the N-terminal kinase domain of RSK by the C-terminal kinase domain, but does not affect the activity of the N-terminal domain, explaining why the active forms of RSK1 and RSK2 are not inhibited by FMK in vitro.[3] FMK,the efficacy and specificity of the irreversible RSK inhibitor in ARVMs and subsequently is used to determine the role of RSK as a direct regulator of NHE1 phosphorylation and sarcolemmal NHE activity in this cell type, in response to  1-adrenergic stimulation.[4] FMK-pa, a propargylamine variant, achieves selective and saturable modification of endogenous RSK1 and RSK2 in mammalian cells. Saturating concentrations of fmk-pa inhibited Ser386 phosphorylation and downstream signaling in response to phorbol ester stimulation, but had no effect on RSK activation by lipopolysaccharide.[5]
Metastasis, the spreading of cancer cells from a primary tumor to secondary sites throughout the body, is driven by altered signaling pathways that induce changes in cell-cell adhesion, the cytoskeleton, integrin function, protease expression, epithelial-to-mesenchymal transition and cell survival.[6] The ribosomal S6 kinase (RSK) family of kinases is a group of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) effectors that can regulate these steps of metastasis by phosphorylating both nuclear and cytoplasmic targets. Thus, developing RSK inhibitors as new antimetastasis drugs is urgent.Recently, RSKs have been shown to mediate many cellular functions critical for cancer progression. RSK may be an important driver in PCa progression in bone which regulates anchorage-independent growth through transcriptional regulation of factors that modulate cell survival, including ING3, CKAP2 and PTK6,resulting in promising potential as a therapeutic target for PCa bone metastasis.[7]
Reference:
1.Michael S. Cohen. et al. Structural Bioinformatics-Based Design of Selective, Irreversible Kinase Inhibitors. Science,2005,308(5726):1318-1321.
2.Frodin M, Gammeltoft S. Role and regulation of 90 kDa ribosomal S6 kinase (RSK) in signal transduction. Mol Cell Endocrinol. 1999, 151(1-2):65-77.
3.Jenny BAIN.et al. The selectivity of protein kinase inhibitors: a further update. Biochem. J. 2007, 408:297-315.
4.Cuello F.et al. Evidence for direct regulation of myocardial Na+/H+ exchanger isoform 1 phosphorylation and activity by 90-kDa ribosomal S6 kinase (RSK): effects of the novel and specific RSK inhibitor fmk on responses to alpha1-adrenergic stimulation. Mol Pharmacol. 2007, 71(3):799-806.
5.Michael S Cohen, Haralambos Hadjivassiliou1, and Jack Taunton. A clickable inhibitor reveals context-dependent autoactivation of p90 RSK. Nat Chem Biol. 2007,3(3): 156-160.
6.Sulzmaier FJ1, Ramos JW. RSK isoforms in cancer cell invasion and metastasis.Cancer Res. 2013,73(20):6099-105.
7.Yu G, Lee YC1. et al. RSK Promotes Prostate Cancer Progression in Bone through ING3, CKAP2 and PTK6-mediated Cell Survival. Mol Cancer Res.2014,0384.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt342.37
Cas No.821794-92-7
FormulaC18H19FN4O2
Synonymsfluoromethylketone-pyrrolopyrimidine scaffold
Solubility≥17.1 mg/mL in DMSO, ≥28.7 mg/mL in EtOH, <1.74 mg/mL in H2O
Chemical Name1-[4-amino-7-(3-hydroxypropyl)-5-(4-methylphenyl)pyrrolo[2,3-d]pyrimidin-6-yl]-2-fluoroethanone
SDFDownload SDF
Canonical SMILESCC1=CC=C(C=C1)C2=C(N(C3=C2C(=NC=N3)N)CCCO)C(=O)CF
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

细胞实验 [1]:

细胞系

Ba/F3细胞,表达FGFR3的骨髓瘤细胞系KMS11

溶解方法

该化合物在DMSO中的溶解度大于17.1 mg/mL。若获取更高浓度的溶液,可在37℃下孵育10分钟,随后在超声波浴中摇匀。-20℃以下可储存数月。

反应条件

0.5-10 μM,16和24小时

应用

FMK以剂量依赖的方式有效抑制FGFR3 TDII和TEL-FGFR3诱导的Ba/F3细胞的IL-3非依赖性生长。RSK抑制剂FMK抑制由FGFR3赋予的Ba/F3细胞的细胞因子非依赖性增殖。FMK在表达FGFR3的t(4; 14)阳性人骨髓瘤细胞系和原代人骨髓瘤细胞中诱导显著的细胞凋亡。

注意事项

由于实验环境的不同,实际溶解度可能与理论值略有不同,请测试室内所有化合物的溶解度。

References:

[1]. Kang S, Dong S, Gu T L, et al. FGFR3 activates RSK2 to mediate hematopoietic transformation through tyrosine phosphorylation of RSK2 and activation of the MEK/ERK pathway[J]. Cancer cell, 2007, 12(3): 201-214.

生物活性

Description FMK是p90核糖核蛋白S6激酶RSK1和RSK2的高效、高特异性和不可逆的抑制剂。
靶点 RSK1 RSK2        
IC50   15 nM        

质量控制