|3-((1H-吡唑并[3,4-b]吡啶-5-基)乙炔基)-4-甲基-N(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺|CsnPharm

CAS No.: 1257628-77-5

3-((1H-Pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide Catalog No. CSN17632

Synonyms: GZD824;HQP1351;D-824

GZD824 is an orally bioavailable Bcr-Abl inhibitor for Bcr-Abl (WT) and Bcr-Abl (T315I) with IC50 of 0.34 and 0.68 nM, respectively.

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纯度 & 质量文件批次:

靶点选择性

生物活性

实验方案

技术信息

生物活性

靶点 Bcr-Abl

IC50:0.34nM Bcr-Abl (T315I)

IC50:0.68nM
描述Bcr-Abl fusion tyrosine kinase is formed because of a reciprocal chromosomal translocation between chromosomes 9 and 22, producing the Philadelphia chromosome. Bcr-Abl is expressed in chronic myeloid leukemia(CML) and a chronic of acute lymphocytic leukemia^[3]. GZD824 is an orally bioavailable inhibitor against a broad spectrum of Bcr-Abl mutants including Bcr-Abl^WT and Bcr-Abl^T315I with Kd values of 0.32nM and 0.71nM, respectively, and with IC50 values of 0.34nM and 0.68nM, respectively. In vitro, GZD824 potently suppressed proliferation of Bcr-Abl positive human CML cell lines K562 , Ku812, SUP-B15, U-937, MOLT4 and HL-60 with IC50 values of 0.2nM, 0.13nM, 2.5nM, 390.2nM, 26.3nM, and348.9nM, respectively. GZD824 suppressed the activation of Bcr-Abl and downstream Crk1 and STAT5 in a dose-dependent manner in K562 cells. In vivo, oral administration of GZD824 at 5 and 10mg/kg once daily for 14 consecutive days significantly suppressed tumor growth in mice bearing xenografted K562 cells. Oral administration of GZD824 at 1mg/kg once daily for 14 days induced complete tumor regression in mice bearing xenografted Ku812 cells. In addition, treatment of the mice bearing xenografted Ba/F3 cells expressing Bcr-Abl ^T315I with GZD824 at dose of 20mg/kg once daily via oral administration for 14 days induced almost complete tumor regression^[1].
作用机制GZD824 inhibits the activation of Bcr-Abl by binding to the ATP-binding site of nonphosphorylated(DGF-out) Bcr-Abl^[1].

动物研究

剂量

Mice: 25 mg/kg^[2] (i.g.) Rat: 25 mg/kg^[1] (p.o.); 5 mg/kg^[1] (i.v.)

给药途径

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

动物药代数据

Animal	Rats^[1]
Dose	5 mg/kg (i.v.) 25 mg/kg (p.o.)
Administration	i.v. p.o.
MRT	6.7 h (i.v.) 17.9 h (p.o.)
F	48.7% (p.o.)
T_1/2	5.6 h (i.v.) 10.6 h (p.o.)
T_max	0.067 h (i.v.) 4.0 h (p.o.)
CL	1.7 L/h/kg (i.v.) 3.6 L/h/kg (p.o.)
C_max	1375.6 μg/L (i.v.) 390.5 μg/L (p.o.)
AUC_0→∞	2922.4 μg·h/L (i.v.) 7108.2 μg·h/L (p.o.)
Vss	13.7 L/h/kg (i.v.) 53.2 L/h/kg (p.o.)
AUC_0→t	2737.3 μg·h/L (i.v.) 6699.0 μg·h/L (p.o.)

参考文献

[1] Ren X, Pan X, Zhang Z, et al. Identification of GZD824 as an orally bioavailable inhibitor that targets phosphorylated and nonphosphorylated breakpoint cluster region-Abelson (Bcr-Abl) kinase and overcomes clinically acquired mutation-induced resistance against imatinib. Journal of Medicinal Chemistry, 2013, 56(3): 879-894
[2] Ye W, Jiang Z, et al. GZD824 suppresses the growth of human B cell precursor acute lymphoblastic leukemia cells by inhibiting the SRC kinase and PI3K/AKT pathways. Oncotarget. 2016 Jul 28;8(50):87002-87015.
[3] Skorski T. BCR-ABL1 Kinase: Hunting an Elusive Target with New Weapons. Chemistry & Biology, 2011, 18(11): 1352-1353

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
- 1.8777 mL
- 9.3886 mL
- 18.7772 mL
- 5 mM
- 0.3755 mL
- 1.8777 mL
- 3.7554 mL
- 10 mM
- 0.1878 mL
- 0.9389 mL
- 1.8777 mL

技术信息

CAS号

1257628-77-5

储存条件

粉末: Sealed in dry,2-8°C

液体: -20°C:3-6 月 -80°C:12月

分子式

C29H27F3N6O

运输

蓝冰

分子量

532.56

别名

GZD824;HQP1351;D-824

溶解度

DMSO	100.0 mg/mL (187.8 mM)

动物实验配方

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靶点	Description	IC50
Bcr-Abl		IC50:0.34nM
Bcr-Abl (T315I)		IC50:0.68nM

3-((1H-Pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide Catalog No. CSN17632

靶点选择性

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