TOK-001
mRNA synthesis
In vitro transcription of capped mRNA with modified nucleotides and Poly(A) tail
Tyramide Signal Amplification (TSA)
TSA (Tyramide Signal Amplification), used for signal amplification of ISH, IHC and IC etc.
Phos Binding Reagent Acrylamide
Separation of phosphorylated and non-phosphorylated proteins without phospho-specific antibody
Cell Counting Kit-8 (CCK-8)
A convenient and sensitive way for cell proliferation assay and cytotoxicity assay
SYBR Safe DNA Gel Stain
Safe and sensitive stain for visualization of DNA or RNA in agarose or acrylamide gels.
Inhibitor Cocktails
Protect the integrity of proteins from multiple proteases and phosphatases for different applications.
TOK-001(Galeterone)是一种新型小分子,选择性靶向CYP17和雄激素受体,用于治疗前列腺癌 [1]。
CYP17和雄激素受体(AR)是前列腺癌治疗期间的两个优选的靶标:前者是负责产生诱导癌症的雄激素的主要酶[1],而后者作为转录因子,其增加雄激素反应性基因的表达[2]。
Galeterone是一种小分子治疗剂,从三种不同的途径治疗前列腺癌:通过竞争性抑制CYP17的酶功能,通过结合AR减少雄激素反应基因表达,并下调AR数量[3]。使用转染CYP17的293T细胞,Galeterone孵育18小时后抑制CYP17的裂解酶功能,IC50值为47 nM[3]。在前列腺癌细胞系测定中,galeterone抑制LNCaP和LAPC-4的增殖,IC50分别为6和3 μM[3]。
在接种LAPC4细胞系的小鼠异种移植模型中,与对照组相比,每日皮下注射galeterone(0.15 mmol/ kg,每天两次)分别使肿瘤的平均体积和重量减少超过80%和50%[3]。Galeterone目前进入了去势抗性前列腺癌的III期临床研究。
参考文献:
[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.
Physical Appearance | A solid |
Storage | Store at -20°C |
M.Wt | 388.56 |
Cas No. | 851983-85-2 |
Formula | C26H32N2O |
Solubility | insoluble in H2O; ≥12.4 mg/mL in DMSO; ≥26.5 mg/mL in EtOH |
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 |
SDF | Download SDF |
Canonical SMILES | CC12CCC(CC1=CCC3C2CCC4(C3CC=C4N5C=NC6=CC=CC=C65)C)O |
运输条件 | 蓝冰运输或根据您的需求运输。 |
一般建议 | 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。溶液形式一般不宜长期储存,请尽快用完。 |
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. |
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 |
质量控制和MSDS
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