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4-[4-(2,3-二氢-1,4-苯并二氧杂环己-6-基)-5-(2-吡啶基)-1H-咪唑-2-基]苯甲酰胺

用途

D4476是具有有效性,选择性和细胞渗透性的CK1抑制剂,其在体外实验的IC50值为0.3 μM。

名称

[ CAS 号 ]:
301836-43-1

[ 中文名 ]:
4-[4-(2,3-二氢-1,4-苯并二氧杂环己-6-基)-5-(2-吡啶基)-1H-咪唑-2-基]苯甲酰胺

[ 英文名 ]:
D4476

[英文别名 ]:

CK1 Inhibitor
Casein Kinase I Inhibitor
D4476

生物活性

[ 描述 ]:

D4476是具有有效性,选择性和细胞渗透性的CK1抑制剂,其在体外实验的IC50值为0.3 μM。

[ 相关类别 ]:

信号通路 >> 自噬 >> 自噬

信号通路 >> 细胞周期/DNA损伤 >> 酪蛋白激酶

信号通路 >> 干细胞及 Wnt 通路 >> 酪蛋白激酶

研究领域 >> 癌症

[ 靶点 ]

CK1:0.3 μM (IC50)

[体外研究]

D4476在体外和细胞中是CK1的有效且相当选择性的抑制剂。在H4IIE肝癌细胞中,D4476特异性抑制其MPD内Ser322和Ser325上内源性叉头盒转录因子O1a(FOXO1a)的磷酸化,而不影响其他位点的磷酸化。使用磷酸化肽在0.1mM ATP下测定CK1δ对应于FOXO1a的残基312-325的TFRPRTSpSNASTIS被抑制,IC50值为0.3μM。随着ATP浓度的降低,CK1δ的IC50值逐渐降低,表明D4476是CK1的ATP竞争性抑制剂。 CK1 [1]。

[细胞实验]

D4476用于抑制Csnk1a1。在补充有10ng / mL mIL-3的培养基中，将D4476加入在96孔板（每孔5,000个细胞）中培养的白血病细胞中。通过向细胞培养物中添加2.5μM，5μM，10μM，20μM和40μMD4476进行D4476剂量滴定，最终DMSO百分比为0.4％。类似地，将D4476加入在补充有mTpo和mScf的SFEM培养基中培养的LSK细胞中。使用流式细胞仪用CountBright绝对计数珠评估处理96小时后的细胞数[2]。

[参考文献]

[1]. Rena G, et al. D4476, a cell-permeant inhibitor of CK1, suppresses the site-specific phosphorylation and nuclear exclusion of FOXO1a. EMBO Rep. 2004 Jan;5(1):60-5.

[2]. Järås M, et al. Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia. J Exp Med. 2014 Apr 7;211(4):605-12.

[相关活性小分子]

Silmitasertib (CX-4945) | 4,5,6,7-四溴苯甲腈 | 2-二甲基氨基-4,5,6,7-四溴苯并咪唑 | 大黄素 | 4-[1-环己基-4-(4-氟苯基)-1H-咪唑-5-基]-2-嘧啶胺盐酸盐 | SR-3029 | IC261 | TA-01 | 鞣花酸 | TTP 22 | LH846 | 酪蛋白激酶II抑制剂IV | PF-4800567

物理化学性质

[ 密度 ]:
1.3±0.1 g/cm3

[ 沸点 ]:
675.0±55.0 °C at 760 mmHg

[ 分子式 ]:
C₂₃H₁₈N₄O₃

[ 分子量 ]:
398.414

[ 闪点 ]:
362.0±31.5 °C

[ 精确质量 ]:
398.137878

[ PSA ]:
103.12000

[ LogP ]:
3.84

[ 外观性状 ]:
固体

[ 蒸汽压 ]:
0.0±2.1 mmHg at 25°C

[ 折射率 ]:
1.663

[ 储存条件 ]:
2-8°C

MSDS

详细MSDS(安全技术说明书)

安全信息

[ 个人防护装备 ]:
Eyeshields;Gloves;type N95 (US);type P1 (EN143) respirator filter

[ 危险品运输编码 ]:
NONH for all modes of transport

文献

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