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Birinapant (TL32711)

现货
Catalog No.
A4219
XIAP/cIAP1拮抗剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,250.00
现货
5mg
¥ 900.00
现货
10mg
¥ 1,400.00
现货
25mg
¥ 2,350.00
现货
50mg
¥ 3,350.00
现货

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Background

Birinapant, also called TL32711, is a potent antagonist for XIAP with Kd value of 45 nM and cIAP1 with Kd value <1 nM [1].
Birinapant not only binds to the isolated BIR3 domains of cIAP1, cIAP2, XIAP but the single BIR domain of ML-IAP with high affinity and degrades TRAF2-bound cIAP1 and cIAP2 rapidly accordingly inhibiting the activation of TNF-mediated NF- kB. Additionally, birinapantcan promote the formation of caspase-8: RIPK1 complex in response to TNF stimulation, which result in downstream caspasesactivation [4].
In the inorganic SUM149- and SUM190-derived cells, which with differential XIAP expression (SUM149 wtXIAP, SUM190 shXIAP) and other high cIAP1/2 but low XIAP binding affinity bivalent Smac mimetic GT13402, XIAP inhibition are needed for increasing TRAIL potency. Opposite, single agent efficacy of Birinapant is owing to pan-IAP antagonism. Rapid cIAP1 degradation was caused by birinapant, as well as NF-κB activation, PARP cleavage andcaspase activation. While combined withTNF-α, showing strong combination activity, the combination was more effective than individual. The response in spheroid models was conserved, whereas in vivo birinapant inhibited tumor growth without adding TNF-α in vitro to resistant cell lines. In a parental cell line, TNF-αcombined withbirinapantinhibited the growth of a melanoma cell line with acquired resistance to the same extent of BRAF inhibition [1, 2].
Drug treatment increased the mean [18F]ICMT-11 tumor uptake with a peak at 24 hours for CPA (40 mg/kg; AUC40-60: 8.04 ± 1.33 and 16.05 ± 3.35 %ID/mL × min at baseline and 24 hours, respectively) and 6 hours for birinapant (15 mg/kg; AUC40-60: 20.29 ± 0.82 and 31.07 ± 5.66 %ID/mL × min, at baseline and 6 hours, respectively). Voxel-based spatiotemporal analysis of tumor-intrinsic heterogeneity showed that [18F] ICMT-11 could detect the discrete pockets of caspase-3 activation. Caspase-3 activation that measured ex vivo associated with the increased tumor [18F] ICMT-11, and early radiotracer uptake predicted apoptosis, distinct from the glucose metabolism with [18F] fluorodeoxyglucose-PET, which depicted the continuous loss of cell viability [3].
References:
1.Allensworth JL, Sauer S, Lyerly HK, et al. Smac mimetic Birinapant induces apoptosis and enhances TRAIL potency in inflammatory breast cancer cells in an IAP-dependent and TNF-a-independent mechanism. Breast Cancer Research, 2013, 137:359-371.
2.Krepler C, Chunduru SK, Halloran MB, et al. The novel SMAC mimetic birinapant exhibits potent activity against human melanoma cells. Clinical Cancer Research, 2013, 19 (7): 1784-1794.
3.Nguyen QD, Lavdas I, Gubbins J, et al. Temporal and Spatial Evolution of Therapy-Induced Tumor Apoptosis Detected by Caspase-3–Selective Molecular Imaging. Clinical Cancer Research, 2013, 19 (14): 3914-3924.
4.Benetatos CA, Mitsuuchi Y, Burns JM, et al. Birinapant (TL32711), a Bivalent SMAC Mimetic, Targets TRAF2-Associated cIAPs, Abrogates TNF-Induced NF-kB Activation, and Is Active in Patient-Derived Xenograft Models. 2014, 13(4):867-879.

文献引用

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt806.94
Cas No.1260251-31-7
FormulaC42H56F2N8O6
Solubility≥40.35 mg/mL in DMSO, ≥46.9 mg/mL in EtOH, <2.34 mg/mL in H2O
Chemical Name(2S,2'S)-N,N'-((2S,2'S)-((3S,3'S,5R,5'R)-5,5'-((6,6'-difluoro-1H,1'H-[2,2'-biindole]-3,3'-diyl)bis(methylene))bis(3-hydroxypyrrolidine-5,1-diyl))bis(1-oxobutane-2,1-diyl))bis(2-(methylamino)propanamide)
SDFDownload SDF
Canonical SMILESCCC(C(=O)N1CC(CC1CC2=C(NC3=C2C=CC(=C3)F)C4=C(C5=C(N4)C=C(C=C5)F)CC6CC(CN6C(=O)C(CC)NC(=O)C(C)NC)O)O)NC(=O)C(C)NC
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

SUM149和SUM190炎症性乳腺癌细胞

制备方法

溶解度有限。若配制更高浓度的溶液,一般步骤如下:请将试管置于37℃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℃可放置数月

反应条件

24 h-96 h

实验结果

Birinapant引起cIAP1和2的明显降解,添加TRAIL不能使其增强。与SUM149中的GT13402相比,Birinapant在增加TRAIL效能方面更有效。此外,Birinapant以剂量依赖性方式显著降低SUM190细胞的活力。

动物实验[2]:

动物模型

黑色素瘤肿瘤异种移植小鼠

给药剂量

腹腔注射,30 mg/kg

制备方法

溶于12.5%Captisol的蒸馏水溶液中

实验结果

与对照相比,在Birinapant处理的小鼠中,cIAP1蛋白在3小时后降低至低水平,作用持续24小时。在相同肿瘤的活检中,对活化的caspase-3进行染色,与对照相比,在处理后24小时,Birinapant处理的小鼠中的凋亡细胞有所增加。

注意事项

请测试所有化合物在室内的溶解度,实际溶解度和理论值可能略有不同。这是由实验系统的误差引起的,属于正常现象。

References:

1. Allensworth JL, Sauer SJ, Lyerly HK et al. Smac mimetic Birinapant induces apoptosis and enhances TRAIL potency in inflammatory breast cancer cells in an IAP-dependent and TNF-α-independent mechanism. Breast Cancer Res Treat. 2013 Jan;137(2):359-71.

2. Krepler C, Chunduru SK, Halloran MB et al. The novel SMAC mimetic birinapant exhibits potent activity against human melanoma cells. Clin Cancer Res. 2013 Apr 1;19(7):1784-94.

生物活性

描述 Birinapant是XIAP和cIAP1的拮抗剂,Kd值分别为45 nM和Kd<1 nM。
靶点 XIAP cIAP1        
IC50 45 nM (Kd) <1 nM (Kd)        

质量控制

化学结构

Birinapant (TL32711)

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Birinapant (TL32711)

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Birinapant (TL32711)

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Birinapant (TL32711)

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Birinapant (TL32711)

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Birinapant (TL32711)