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TOK-001

现货
Catalog No.
A8623
CYP17抑制剂和雄激素受体(AR)拮抗剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,000.00
现货
10mg
¥ 1,600.00
现货
50mg
¥ 4,700.00
现货

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Background

TOK-001 (Galeterone) is a novel small molecule that selectively target CYP17 and androgen receptor for prostate cancer treatment [1].

CYP17 and androgen receptor (AR) are two preferred target during the treatment of prostate cancer: The former is the prime enzyme that responsible for the production of cancer-inducing androgens [1], whereas the latter acts as transcription factor that increases the expression of androgen-responsive genes [2].

Galeterone is a small molecular therapeutics that designed to treat prostate cancer in three distinctive pathways: competitively inhibit the enzyme function of CYP17. Decreasing androgen-responsive genes expression by binding to AR, and downregulates AR population [3]. Using 293T cells transfected with CYP17, galeterone inhibited the lyase function of CYP17 with an IC50 value of 47 nM after 18 hrs of incubation [3]. In prostate cancer cell line assay, galeterone inhibited the proliferation of LNCaP and LAPC-4 with IC50 value of 6 and 3 µM, respectively [3].

In mice xenograft model that inoculated with LAPC4 cell lines, a daily subcutaneous injection of galeterone (0.15 mmol/kg, twice per day) reduced both the average volume and weight of tumour less by more than 80% and 50%, respectively in comparison with control group [3]. Galeterone is currently underwent phase III clinical trails for castration-resistant prostate cancer.

References:
[1]. Devore N M, & Scott E E. Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001. Nature, 2012, 482: 116-119.
[2]. Mallik I, Davila M, Tapia T, et al. Androgen regulates Cdc6 transcription through interactions between androgen receptor and E2F transcription factor in prostate cancer cells. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2008,1783:1737-1744.
[3]. Bruno R D, Vasaitis T S, Gediya L. K, et al. Synthesis and biological evaluations of putative metabolically stable analogs of VN/124-1 (TOK-001): Head to head anti-tumor efficacy evaluation of VN/124-1 (TOK-001) and abiraterone in LAPC-4 human prostate cancer xenograft model. Steroids, 2011,76: 1268-1279.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt388.56
Cas No.851983-85-2
FormulaC26H32N2O
Solubility≥12.4mg/mL in DMSO
Chemical Name(3S,8R,9S,10R,13S,14S)-17-(benzimidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-ol
SDFDownload SDF
Canonical SMILESCC12CCC(CC1=CCC3C2CCC4(C3CC=C4N5C=NC6=CC=CC=C65)C)O
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]:

CYP17体外实验

以完整的表达P450c17的大肠杆菌作为酶源,采用快速醋酸释放实验评估Galeterone对CYP17的体外抑制活性。以[21-3H]-17α-羟基孕烯醇酮作为底物,CYP17活性由底物C-21侧链剪切产生的氚化乙酸数量来衡量。在适当的范围内,根据抑制百分比对抑制剂浓度做图,从而确定IC50值。

细胞实验 [2]:

细胞系

LNCaP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

1 ~ 15 μM;24小时

实验结果

与所有Galeterone类似物相比,Galeterone在体外最有效地下调AR。在15 μM浓度下,Galeterone下调大于95% 的AR。

动物实验 [2]:

动物模型

携带LAPC-4肿瘤的雄性SCID小鼠

给药剂量

0.15 mmol/kg;皮下注射;每日2次,持续31日

实验结果

Galeterone有效抑制SCID小鼠LAPC-4肿瘤的平均体积(超过80%)。在Galeterone治疗31天后,最终肿瘤重量也显着降低超过50%。

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]. Handratta VD, Vasaitis TS, Njar VC, Gediya LK, Kataria R, Chopra P, Newman D Jr, Farquhar R, Guo Z, Qiu Y, Brodie AM. Novel C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens: synthesis, in vitro biological activity, pharmacokinetics, and antitumor activity in the LAPC4 human prostate cancer xenograft model. J Med Chem. 2005 Apr 21;48(8):2972-84.

[2]. Bruno R D, Vasaitis T S, Gediya L. K, et al. Synthesis and biological evaluations of putative metabolically stable analogs of VN/124-1 (TOK-001): Head to head anti-tumor efficacy evaluation of VN/124-1 (TOK-001) and abiraterone in LAPC-4 human prostate cancer xenograft model. Steroids, 2011,76: 1268-1279.

生物活性

Description Galeterone(TOK-001) is a selective inhibitor of CYP17 and antagonist of androgen receptor (AR) with IC50 value of 300 nM and 384 nM, respectively
Targets CYP17 Androgen Receptor        
IC50 300 nM 384 nM        

质量控制

化学结构

TOK-001