|2-氰基-3-(5-(1-环己基-1,6-二氢咪唑并[4,5-d]吡咯并[2,3-b]吡啶-2-基)呋喃-2-基)-N,N-二甲基丙烯酰胺|CsnPharm

CAS No.: 2226521-65-7

FM-381 Catalog No. CSN23319

FM381 is a potent covalent reversible inhibitor of JAK3 targeting the unique Cys909 at the gatekeeper position +7 in JAK3. FM-381 has an IC50 of 127 pM for JAK3, with 410, 2700 and 3600-fold selectivity over JAK1, JAK2 and TYK2, respectively.

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400-920-2911

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靶点选择性

生物活性

实验方案

技术信息

生物活性

描述JAK3 (Janus Kinase 3) is a non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation. JAK3 mediates essential signaling events in both innate and adaptive immunity and plays a crucial role in hematopoiesis during T-cells development. In the cytoplasm, JAK3 plays a pivotal role in signal transduction. Following ligand binding to cell surface receptors, JAK3 phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, JAK3 phosphorylates the STATs proteins once they are recruited to the receptor. FM-381 is a JAK3 selective inhibitor with IC₅₀ of 127pM, while its IC₅₀s against JAK1, JAK2 and TYK2 were 52nM, 346nM and 459nM, respectively^[1]. Using an in cell NanoBRET assay system, the EC₅₀ of FM-381 on JAK3 inhibitory was 237nM, while no effect was detected on JAK1, JAK2 or BTK kinase at the concentration of 10000nM^[2]. In a STAT phosphorylation assay utilizing primary human T-cells, FM-381 showed significant inhibition of IL-2 induced STAT5 phosphorylation at concentrations around 50 to 100nM, reduced IL-4 induced STAT6 phosphorylation at concentrations around 300nM. The JAK3-independent IL-6 induced STAT3 or IFN-α induced STAT1 phosphorylation were not influenced by FM-381 at the concentration up to 1000nM, thus further confirming the selectivity of FM-381 for JAK3^[2].
作用机制Covalent bond formation that could be reversed under physiological conditions were detected between FM-381 and the C909 residue in JAK3 kinase by X-ray structural studies^[2].
参考文献

[1] Forster M, Chaikuad A, Bauer SM, Holstein J, Robers MB, Corona CR, Gehringer M, Pfaffenrot E, Ghoreschi K, Knapp S, Laufer SA. Selective JAK3 Inhibitors with a Covalent Reversible Binding Mode Targeting a New Induced Fit Binding Pocket. Cell Chem Biol. 2016 Nov 17;23(11):1335-1340.
[2] Forster M, Chaikuad A, Dimitrov T, Döring E, Holstein J, Berger BT, Gehringer M, Ghoreschi K, Müller S, Knapp S, Laufer SA. Development, Optimization, and Structure-Activity Relationships of Covalent-Reversible JAK3 Inhibitors Based on a Tricyclic Imidazo[5,4- d]pyrrolo[2,3- b]pyridine Scaffold. J Med Chem. 2018 Jun 28;61(12):5350-5366.

实验方案

计算器摩尔计算器总药量计算器工作液计算器
储存液制备
- 1 mg
- 5 mg
- 10 mg
- 1 mM
- 2.3338 mL
- 11.6690 mL
- 23.3380 mL
- 5 mM
- 0.4668 mL
- 2.3338 mL
- 4.6676 mL
- 10 mM
- 0.2334 mL
- 1.1669 mL
- 2.3338 mL

技术信息

CAS号

2226521-65-7

储存条件

粉末: Sealed in dry,2-8°C

液体: -20°C:3-6 月 -80°C:12月

分子式

C24H24N6O2

运输

蓝冰

分子量

428.49

别名

溶解度

DMSO	32.0 mg/mL (74.7 mM)
Water	insoluble
Ethanol	insoluble

动物实验配方

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