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AT-101

现货
Catalog No.
A3196
BH3-类似物,棉酚对映异构体
组合的产品项目
规格价格库存 数量
10mg
¥ 1,050.00
Ship with 10-15 days
50mg
¥ 3,300.00
Ship with 10-15 days

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Background

AT101, a natural product from cottonseed with a BH3-mimetic structure, was identified as a small molecule inhibitor of Bcl-2/Bcl-xL/Mcl-1 that potently induces apoptosis in various cancer cell lines [1].It is one of the world's first small molecule Bcl-2 inhibitors that has entered into clinical trials and is now in phase II clinical trials for hormone-refractory prostate cancer and other types of cancers [2, 3]. Few side effects of gossypol have been reported, with the major side effects of gossypol being nausea and vomiting in the third month of treatment or rashes earlier in the course of treatment [4]. Thus, AT101 is clinically safe [2, 3] and could be used as a potential inducer of apoptosis in cancer treatment.
As a BH3 mimetic, AT-101 binds to the hydrophobic surface binding groove BH3 of the anti-apoptotic proteins Bcl-2 and Bcl-xL, blocking their heterodimerization with pro-apoptotic members of the Bcl-2 family of proteins such as Bad, Bid, and Bim; this may result in the inhibition of tumor cell proliferation and the induction of tumor cell apoptosis. Preclinical studies revealed that gossypol not only interrupts the interaction between anti- and proapoptotic Bcl-2 family proteins but also induces BH3 protein (such as Puma and Noxa) up-regulation or down-regulates XIAP expression [5]. Thus, gossypol can induce apoptosis by activating apoptogenic factors other than the Bcl-2 family. AT-101 induced apoptosis in vitro through activation of caspase-9.
AT101 delayed onset of androgen-independent growth of VCaP prostate cancer xenografts in vivo. Gossypol can neutralize antiapoptotic Bcl-2 proteins and induced Bax activation [1]. However, the function of gossypol was not limited to effects on the interaction between anti- and proapoptotic Bcl-2 proteins. Some studies have demonstrated that gossypol could down-regulate Bcl-2, Bcl-xL, and XIAP expression [6] or induce Puma and Noxa expression. Therefore, the apoptotic effect of gossypol has been demonstrated to be attenuated by the presence of androgen in a prostate cancer xenograft mouse model.
References:
[1]. Meng Y, Tang W,Dai Y, et al. Natural BH3-mimetic (-)-gossypol chemosensitizes human prostate cancer via Bcl-xL inhibition accompanied by increase of Puma and Noxa.Molecular cancer therapeutics,2008,7(7): 2192–2202.
[2]. Liu G,Kelly W. K,Wilding G,et al. An Open-Label, Multicenter, Phase I/II Study of Single-Agent AT-101 in Men with Castrate-Resistant Prostate Cancer (CRPC).Clinical Cancer Research,2009,15(9): 3172–3176.
[3]. Van Poznak C, Seidman A. D,Reidenberg M,et al. Oral gossypol in the treatment of patients with refractory metastatic breast cancer: a phase I/II clinical trial,Breast Cancer ResTreat ,2001,66(3):239-48.
[4]. Qiu J,Levin L. R,Buck J,et al. Different pathways of cell killing by gossypol enantiomers.Exp Biol Med (Maywood) ,2002,227(6):398-401.
[5]. Balakrishnan K,Burger J. A,Wierda W. G,et al. AT-101 induces apoptosis in CLL B cells and overcomes stromal cell–mediated Mcl-1 induction and drug resistance.Blood,2009,113(1): 149–153.
[6].Sung B,Ravindran J,Prasad S,et al.Gossypol Induces Death Receptor-5 through Activation of the ROS-ERK-CHOP Pathway and Sensitizes Colon Cancer Cells to TRAIL.J Biol Chem,2010,285(46): 35418–35427.

Chemical Properties

Physical AppearanceYellow solid
StorageStore at -20°C
M.Wt518.55
Cas No.90141-22-3
FormulaC30H30O8
Synonyms(R)-(-)-Gossypol;R-(-)-gossypol acetic acid;AT 101;AT101
SolubilitySoluble in DMSO
Chemical Name7-(8-formyl-1,6,7-trihydroxy-3-methyl-5-propan-2-ylnaphthalen-2-yl)-2,3,8-trihydroxy-6-methyl-4-propan-2-ylnaphthalene-1-carbaldehyde
SDFDownload SDF
Canonical SMILESCC1=C(C(=C2C(=C1)C(=C(C(=C2C=O)O)O)C(C)C)O)C3=C(C=C4C(=C3O)C(=C(C(=C4C(C)C)O)O)C=O)C
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

CLL(慢性淋巴性白血病) B细胞

溶解方法

在DMSO中的溶解度>10 mM。为了获得更高的浓度,可以将离心管在37℃加热10分钟和/或在超声波浴中震荡一段时间。原液可以在-20℃以下储存几个月

反应时间

1, 3, 10, 15, 20, 30μm作用 24h; 20μm作用 4, 8, 24 hours

应用

AT-101在CLL B细胞中能够诱导凋亡,克服微环境介导的抵抗,并且不对正常的基质细胞产生影响。AT-101能够导致Mcl-1(骨髓细胞白血病1)切割,呈现时间和剂量的依赖性。全长Mcl-1的降低与膜联蛋白阳性和PARP(聚ADP-核糖聚合酶)切割密切相关。

动物实验[2]:

动物模型

带有来自于Ptch+/-; p53-/-小鼠来源的颅内同种异体移植成神经管细胞瘤的无胸腺裸鼠

剂量

20或 40 mg/kg,每日口服

应用

AT-101的治疗明显抑制了同种异体移植的小鼠成神经管细胞瘤的生长。在体内,AT-101可以通过抑制Hh通路来抑制Hh驱使的成神经管细胞瘤的生长。

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]. Balakrishnan K,Burger J, et al, AT-101 induces apoptosis in CLL B cells and overcomes stromal cell–mediated Mcl-1 induction and drug resistance.Blood,2009,113(1): 149–153.

[2]. Wang J1, Peng Y, et al, AT-101 inhibits hedgehog pathway activity and cancer growth. Cancer Chemother Pharmacol. 2015 Sep;76(3):461-9. doi: 10.1007/s00280-015-2812-x. Epub 2015 Jun 26.

生物活性

Description AT-101是棉酚的R-异构体。
靶点 Bcl-2 Bcl-XL Mcl-1      
IC50            

质量控制

质量控制和MSDS

批次:

化学结构

AT-101