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Danusertib (PHA-739358)

现货
Catalog No.
A4116
Aurora kinase(极光激酶)抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,200.00
Ship with 10-15 days
5mg
¥ 1,100.00
Ship with 10-15 days
10mg
¥ 1,900.00
Ship with 10-15 days
50mg
¥ 5,900.00
Ship with 10-15 days

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Background

Danusertib (previously known as PHA-739358), a 3-aminopyrazole derivative identified during the development of the pyrrolopyrazole sub-series, is a potent small-molecule inhibitor of aurora kinases family members with a dominant inhibition for aurora B kinase (ABK). This pan-aurora kinases inhibitor is also able to inhibit several tyrosine kinases, including T315I mutant, Ret, Trk-A and fibroblast growth factor receptor-1 (FGFR-1), which are involved in multiple malignancies, such as chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), thyroid prostate and breast carcinoma. Thus, in many previous studies, danusertib exhibits remarkable antitumor activity in a number of different xengorafts, spontaneous, and transgenic animal tumor models with a favorable pharmacokinetic and safety profile.

Reference

Carpinelli P, Ceruti R, Giorgini ML, Cappella P, Gianellini L, Croci V, Degrassi A, Texido G, Rocchetti M, Vianello P, Rusconi L, Storici P, Zugnoni P, Arrigoni C, Soncini C, Alli C, Patton V, Marsiglio A, Ballinari D, Pesenti E, Fancelli D, Moll J. PHA-739358, a potent inhibitor of aurora kinases with a selecyive target inhibiton profile relevant to cancer. Mol Cancer Ther 2007; 6(12 Pt 1): 3158-3168

文献引用

1. Wang H, Tian L, et al. "The Osteogenic Niche Is a Calcium Reservoir of Bone Micrometastases and Confers Unexpected Therapeutic Vulnerability." Cancer Cell. 2018 Nov 12;34(5):823-839.e7. PMID:30423299
2. Wang H, Tian L, et al. "Bone-in-culture array as a platform to model early-stage bone metastases and discover anti-metastasis therapies." Nat Commun. 2017 Apr 21;8:15045. PMID:28429794

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt474.55
Cas No.827318-97-8
FormulaC26H30N6O3
Synonyms5-Amido-pyrrolopyrazole 9d
Solubility≥23.75 mg/mL in DMSO, <2.37 mg/mL in EtOH, <2.46 mg/mL in H2O
Chemical NameN-[5-[(2R)-2-methoxy-2-phenylacetyl]-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide
SDFDownload SDF
Canonical SMILESCN1CCN(CC1)C2=CC=C(C=C2)C(=O)NC3=NNC4=C3CN(C4)C(=O)C(C5=CC=CC=C5)OC
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]:

生化激酶实验

首先测定ATP和特异性底物的Km值,在ATP (2Km) 和底物 (5Km) 的最佳浓度下开展每项实验。上述步骤有利于直接比较Danusertib对各种激酶的选择性,计算相应IC50值。

细胞实验 [2]:

细胞系

CD34+细胞

制备方法

在DMSO中的溶解度大于10 mM。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

5 μM;5天

实验结果

在耐IM CML患者的CD34+细胞中,Danusertib诱导细胞凋亡并降低P-CrkL磷酸化。

动物实验 [2]:

动物模型

皮下注射K562细胞的雌性SCID小鼠

给药剂量

15 mg/kg;腹腔注射;每日2次,持续10天

实验结果

Danusertib显著抑制K562细胞增殖和肿瘤生长

其它注意事项

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]. Carpinelli P, Ceruti R, Giorgini ML, Cappella P, Gianellini L, Croci V, Degrassi A, Texido G, Rocchetti M, Vianello P, Rusconi L, Storici P, Zugnoni P, Arrigoni C, Soncini C, Alli C, Patton V, Marsiglio A, Ballinari D, Pesenti E, Fancelli D, Moll J. PHA-739358, a potent inhibitor of aurora kinases with a selecyive target inhibiton profile relevant to cancer. Mol Cancer Ther 2007; 6(12 Pt 1): 3158-3168.

[2]. Gontarewicz A, Balabanov S, Keller G, Colombo R, Graziano A, Pesenti E, Benten D, Bokemeyer C, Fiedler W, Moll J, Brümmendorf TH. Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I. Blood. 2008 Apr 15;111(8):4355-64.

生物活性

描述 Danusertib(PHA-739358)是Aurora激酶的抑制剂,对Aurora A/B/C的IC50 值分别为13 nM、79 nM和61 nM,对于Abl、TrkA、c-RET和 FGFR1具有中度抑制效果,对Lck、VEGFR2/3、c-Kit和CDK2等的抑制作用较小。
靶点 Aurora A/B/C Bcr-Abl c-RET FGFR TrkA  
IC50 13 nM/79 nM/61 nM 25nM 31 nM 47 nM 30 nM  

质量控制

化学结构

Danusertib (PHA-739358)

相关生物数据

Danusertib (PHA-739358)

相关生物数据

Danusertib (PHA-739358)

相关生物数据

Danusertib (PHA-739358)

相关生物数据

Danusertib (PHA-739358)