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DCC-2036 (Rebastinib)

Catalog No.
B1404
Bcr-Abl抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,210.00
Ship with 10-15 days
5mg
¥ 1,040.00
Ship with 10-15 days
10mg
¥ 1,570.00
Ship with 10-15 days
50mg
¥ 6,270.00
Ship with 10-15 days

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Background

DCC-2036 is a conformational control inhibitor of ABL1 with IC50 value of 0.8nM [1].

DCC-2036 is synthesized as a dual-anchoring inhibitor that binds both the switch control pocket E282/R386 pair and the Met318 ATP hinge. It shows a IC50 value of 0.8nM. DCC-2036 also exerts potent inhibition of the gatekeeper mutant ABL1T315I with IC50 value of 4nM. DCC-2036 inhibits ABL1 through forcing the kinase domains into inhibitor-bound, inactive Type II conformations. For the purified ABL1, DCC-2036 strongly inhibits unphosphorylated native ABL1, phosphorylated native ABL1, ABL1H396P, unphosphorylated ABL1T315I and phosphorylated ABL1T315I with IC50 values of 0.82nM, 2nM, 1.4nM, 5nM and 4nM, respectively. It is found that DCC-2036 inhibits ABL1 in a non-ATP-competitive manner. In cellular assay, DCC-2036 inhibits the proliferation of Ba/F3 and K562 cells with IC50 values of 5.4nM and 5.5nM, respectively. Moreover, treatment of DCC-2036 can effectively prolong survival in mice bearing Ba/F3-BCR-ABL1T315I leukemia cells. DCC-2036 is also capable to inhibit BCR-ABL1 in primary leukemic cells from patients with Ph+ leukemia [1].

References:
[1] Chan W W, Wise S C, Kaufman M D, et al. Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036. Cancer cell, 2011, 19(4): 556-568.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt553.59
Cas No.1020172-07-9
FormulaC30H28FN7O3
Solubility≥27.7mg/mL in DMSO
Chemical Name4-[4-[(5-tert-butyl-2-quinolin-6-ylpyrazol-3-yl)carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide
SDFDownload SDF
Canonical SMILESCC(C)(C)C1=NN(C(=C1)NC(=O)NC2=C(C=C(C=C2)OC3=CC(=NC=C3)C(=O)NC)F)C4=CC5=C(C=C4)N=CC=C5
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

表达天然或突变BCRABL1的Ba/F3细胞

制备方法

在DMSO中的溶解度大于27.7 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

2 ~ 150 nM

实验结果

在表达天然BCR-ABL1native的Ba/F3细胞中,DCC-2036有效抑制细胞增殖,其IC50值为5.4 nM。在耐Imatinib、Dasatinib (T315A) 和Nilotinib (L248R、Y253H、E255V和F359C)的表达突变BCRABL1的Ba/F3细胞中,DCC-2036也有效抑制细胞增殖。此外,在对FDA批准的3种TKI都无效的BCR-ABL1T315I突变体中,DCC-2036仍然有效(IC50 = 13 nM)。

动物实验 [1]:

动物模型

携带Ba/F3-BCR-ABL1T315I白血病细胞的小鼠

给药剂量

100 mg/kg;口服给药

实验结果

在携带Ba/F3-BCR-ABL1T315I白血病细胞的小鼠中,单次口服给予100 mg/kg DCC-2036能使药物血浆浓度在24小时内持续高于12 μM,并持续有效抑制BCR-ABL1信号传导(高达8小时)。给予100 mg/kg DCC-2036,每天1次,显著延长携带Ba/F3-BCR-ABL1T315I白血病细胞的小鼠的存活期。

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]. Chan W W, Wise S C, Kaufman M D, et al. Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036. Cancer cell, 2011, 19(4): 556-568.

生物活性

Description DCC-2036(Rebastinib)是一种Bcr-Abl抑制剂,对Abl1(WT)和Abl1(T315I)的IC50值分别为0.8 nM和4 nM.
靶点 u-Abl1 (native) Abl1 (H396P) p-Abl1 (native) FLT3 p-Abl1 (T315I)  
IC50 0.75 nM 1.4 nM 2 nM 2 nM 4 nM  

质量控制

质量控制和MSDS

批次:

化学结构

DCC-2036 (Rebastinib)