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CAS No.: 1832671-96-1

Y06036 Catalog No. CSN24058

Synonyms: Y06036

Y06036 is a potent and selective BET inhibitor with BRD4(1) bromodomain binding Kd value of 82 nM. It has antitumor activity and could be used for Potential Treatment of Castration-Resistant Prostate Cancer (CRPC).

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400-920-2911

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实验方案

技术信息

生物活性

描述Bromodomain and extra terminal domain (BET) family proteins, including BRD2, BRD3, BRD4, and BRDT, bind to acetylated lysines via their tandem domains (BD1 and BD2) to regulate gene transcription. These proteins have emerged as new therapeutic targets for human diseases and conditions, including cancers and inflammation. Y06036 is a potent BET bromodomain inhibitor which bounds to the BRD4(1) bromodomain with Kd values of 82 nM. The compound also potently inhibited cell growth, colony formation, and the expression of AR, AR regulated genes, and MYC in prostate cancer cell lines. In C4-2B CRPC xenograft mice, mice were treated with intraperitoneal injections of vehicle or Y06036 at a dose of 50 mg/kg 5 times per week. The efficacy data showed that Y06036 exhibited strong antitumor activities during the 25-day treatment period, with a tumor growth inhibition (TGI) of 70%. To evaluate cytotoxicity for various cell lines, Y06036 was evaluated in a wide range of cancer cell lines. Y06036 was potent in AR-negative prostate cancer cells DU145 with IC₅₀ > 6 μΜ and PC-3 with IC₅₀ > 3 μΜ. Besides, the breast cancer cells MCF-7 and Hs578T also appeared to be sensitive to Y06036 and IC₅₀s are 1 and 2.5 μΜ. The studies still showed that Y06036 displayed moderate (2.5 - 5 μΜ) or weak (> 5 μΜ) inhibitory effects in the rest of cancer cell lines. Further more, Y06036 exhibited weak cytotoxicity in the normal lung fibroblast cell line HFL-1 with IC₅₀ values of 18.2 μΜ and 15.9 μΜ^[2].
作用机制Y06036 binds to the BRD4(1) bromodomain and forms hydrogen bond interactions with the seventh solvent water molecule. Importantly, the 6-OCH3 of Y06036 occupied the position of the acetylated lysine (K5Ac) hydrophobic chain^[2].

动物研究

剂量

Mice: 50 mg/kg^[1] (i.p.) Rat: 2 mg/kg^[1] (i.v.); 10 mg/kg^[1] (p.o.)

给药途径

i.p., i.v., p.o.

动物药代数据

Animal	Rats^[1]
Dose	2 mg/kg (i.v.) 10 mg/kg (p.o.)
Administration	i.v. p.o.
F	2.38
MRT_0→t	0.90 h (i.v.) 1.88 h (p.o.)
T_1/2	1.93 h (i.v.) 1.56 h (p.o.)
V_z	4.78 L/kg (i.v.)
T_max	0.08 h (i.v.) 0.50 h (p.o.)
CL	1.71 L/h/kg (i.v.)
C_max	1392.28 μg/L (i.v.) 76.46 μg/L (p.o.)
AUC_0→∞	1168.92 μg/L·h (i.v.) 139.39 μg/L·h (p.o.)
AUC_0→t	1154.97 μg/L·h (i.v.) 134.42 μg/L·h (p.o.)

参考文献

[1] Zhang M, Zhang Y, et al. Structure-Based Discovery and Optimization of Benzo[ d]isoxazole Derivatives as Potent and Selective BET Inhibitors for Potential Treatment of Castration-Resistant Prostate Cancer (CRPC). J Med Chem. 2018 Apr 12;61(7):3037-3058.
[2] Zhang M, Zhang Y, Song M, Xue X, Wang J, Wang C, Zhang C, Li C, Xiang Q, Zou L, Wu X, Wu C, Dong B, Xue W, Zhou Y, Chen H, Wu D, Ding K, Xu Y. Structure-Based Discovery and Optimization of Benzo[ d]isoxazole Derivatives as Potent and Selective BET Inhibitors for Potential Treatment of Castration-Resistant Prostate Cancer (CRPC). J Med Chem. 2018 Apr 12;61(7):3037-3058.

实验方案

计算器摩尔计算器总药量计算器工作液计算器
储存液制备
- 1 mg
- 5 mg
- 10 mg
- 1 mM
- 2.3404 mL
- 11.7022 mL
- 23.4044 mL
- 5 mM
- 0.4681 mL
- 2.3404 mL
- 4.6809 mL
- 10 mM
- 0.2340 mL
- 1.1702 mL
- 2.3404 mL

技术信息

CAS号

1832671-96-1

储存条件

粉末: Keep in dark place,Inert atmosphere,Room temperature

液体: -20°C:3-6 月 -80°C:12月

分子式

C16H15BrN2O5S

运输

蓝冰

分子量

427.27

别名

Y06036

溶解度

DMSO	85.0 mg/mL (198.9 mM)
Water	Insoluble
Ethanol	Insoluble

动物实验配方

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