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PF-3758309

现货
Catalog No.
A3716
PAK4抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 600.00
现货
10mg
¥ 790.00
现货
50mg
¥ 2,350.00
Ship with 10-15 days

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Background

PF-3758309 is an inhbitor of PAK4 with IC50 of 1.3 nM [1].

P21-activated kinases (PAKs) are the family of serine/theronine kinases, which play important role in linking Rho GTPase to cytoskeleton reorganization and nuclear signaling. PAK4 is a member of PAKs family, specifically responsive for interacting with GTP bound form of Cdc42 and JNK family. PAK4 is involved in filopodia formation and may play a role in the reorganization of the actin cytoskeleton.

Biochemical study had identified that PF-3758309 was an ATP-competitive inhibitor of PAK4, which inhibited the kinase activity [1]. When PAK4 was screened with a panel of tumor cell lines, it was found PF-3758309 inhibited the phosphorylation of PAK4 substrate GEF-H1, and also the PAK4-induced anchorage-independent cell growth, with IC50 value of 1.3 nM and 4.7 ±3 nM respectively [1]. When PF-3758309 was screened with a panel of PAKs related kinases, it exhibited good potency and specificity for PAK4 [1]. Cell analysis confirmed that PF-3758309 modulates PAK4-dependent signaling nodes and identifies unexpected links to additional p53pathways [1].

In vivo activity of PF-3758309 was examined in a panel of human xenograft model, including HCT116 and A549 model. Twice daily oral administration of PF-3758309 (7.5-30 mg/kg BID) for 9-18 days resulted in significant inhibition of tumor growth in all the models. The tumor growth was shown to be caused by PAK-dependent pathways in HCT116 and A549 model. Additionally, PF-3758309 was shown to regulate PAK-associated cell proliferation and survival in certain models. Therefore, PF-3758309 exhibited inhibitory activity on PAK4 [1].

Reference:
[1] Murray B W et al. , Small-molecule p21-activated kinase inhibitor PF-3758309 is a potent inhibitor of oncogenic signaling and tumor growth. Proc Natl Acad Sci USA. 2010, 107(20): 9446-9451.

文献引用

1. White SM, Avantaggiati ML, et al. "YAP/TAZ Inhibition Induces Metabolic and Signaling Rewiring Resulting in Targetable Vulnerabilities in NF2-Deficient Tumor Cells." Dev Cell. 2019 May 6;49(3):425-443.e9. PMID:31063758
2. Ramos-Alvarez I, Jensen RT. "P21-activated kinase 4 in pancreatic acinar cells is activated by numerous gastrointestinal hormones/neurotransmitters and growth factors by novel signaling, and its activation stimulates secretory/growth cascades." Am J Physiol Gastrointest Liver Physiol. 2018 Aug 1;315(2):G302-G317. PMID:29672153

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt490.62
Cas No.898044-15-0
FormulaC25H30N8OS
SynonymsPF 3758309; PF3758309
Solubility≥24.53 mg/mL in DMSO, ≥101.4 mg/mL in EtOH with ultrasonic and warming, <2.11 mg/mL in H2O
Chemical NameN-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methylthieno[3,2-d]pyrimidin-4-yl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide
SDFDownload SDF
Canonical SMILESCC1=NC2=C(C(=N1)NC3=NNC4=C3CN(C4(C)C)C(=O)NC(CN(C)C)C5=CC=CC=C5)SC=C2
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

激酶实验 [1]:

磷酸-GEF-H1细胞试验

使用稳定转染四环素诱导的PAK4激酶域(氨基酸291 ~ 591)以及持续表达HA标记的GEFH1ΔDH(氨基酸210 ~ 921)的HEK293细胞来构建TR-293-KDG细胞。将TR-293-KDG细胞与PF-3758309一起孵育3小时,将其加入到含抗HA抗体的实验板上,使用抗磷酸-S810-GEF-H1抗体进行测定,并通过辣根过氧化物酶标记山羊抗兔抗体结合物进行定量。

细胞实验 [1]:

细胞系

HEK293T细胞、HCT116细胞和 SKOV3 细胞

制备方法

在DMSO中的溶解度大于24.5 mg/mL。若配制更高浓度的溶液,一般步骤如下:请将试管置于37 °C加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20 °C可放置数月。

反应条件

1 μM;72小时

实验结果

在测试的细胞系中,PF-3758309抑制PAK4底物GEF-H1的磷酸化和锚定非依赖生长。此外,PF-3758309还抑制内源性pGEF-H1在HCT116细胞中积累。

动物实验 [1]:

动物模型

一系列人异种移植肿瘤模型

给药剂量

7.5 ~ 30 mg/kg;口服给药;每天2次,持续9 ~ 18天

实验结果

在5个模型(包括PAK4依赖性的HCT116和A549模型)中,PF-3758309显著抑制肿瘤生长。另一方面,PF-3758309对DLD1细胞(PAK4等位基因中的一个发生功能丧失性突变)没有显示出抑制作用。

注意事项

请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同,但仍处于实验系统误差的允许范围内。

References:

[1]. Murray B W et al. Small-molecule p21-activated kinase inhibitor PF-3758309 is a potent inhibitor of oncogenic signaling and tumor growth. Proc Natl Acad Sci USA. 2010, 107(20): 9446-9451.

生物活性

Description PF-03758309是一种有效的和ATP竞争性的吡咯并吡唑类PAK4抑制剂,其IC50值为1.3 nM。
靶点 PAK4          
IC50 Ki=18.7 nM, Kd = 2.7 nM          

质量控制

质量控制和MSDS

批次:

化学结构

PF-3758309

相关生物数据

PF-3758309