|N-(环丙基甲基)-2-(4-(4-甲氧基苯甲酰基)哌啶-1-基)-N - ((4-氧代-4,5,7,8-四氢-3H-吡喃并[4,3-d]嘧啶-2-基)甲基)乙酰胺|CsnPharm

CAS No.: 1419949-20-4

NVP-TNKS656 Catalog No. CSN13750

Synonyms: TNKS656

NVP-TNKS656 is a highly potent, selective, and orally active TNKS2 inhibitor with IC50 of 6 nM, showing > 300 fold selectivity against PARP1 and PARP2.

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400-920-2911

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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

描述Tankyrase 1 and 2 have been shown to be redundant, druggable nodes in the Wnt pathway. NVP-TNKS656 is a novel and selective tankyrase 2 inhibitor with IC50 value of 6nM, while exhibits inhibitory effect on PARP 1 and 2 with IC50 values up to >19μM and 32μM, respectively. NVP-TNKS656 exhibited a good PK/PD relationship as a corresponding 70−80% reduction in the Wnt/beta-catenin target gene Axin2 mRNA level, compared to vehicle control animals, could be observed in MMTV-Wnt1 tumor bearing athymic nude mice after a single oral dose of NVP-TNKS656 at 350 mg/kg over a 24-h time. Inhibition of Tankyrases through NVP-TNKS656 could potentiate MEK inhibitor activity by releasing a FGFR2 signaling feedback loop, as well as synergize with MEK inhibitor to downregulate FGFR2 signaling and enhance antitumor activity in vivo. Intraperitoneal injection with 100mg/kg twice daily blocked the Wnt/β-catenin signaling in colorectal cancer PDX models shown by reduction of nuclear β-catenin and increase of AXIN1 protein levels.
作用机制NVP-TNKS656 could bind to the pocket of tankyrase.^[1]

动物研究

剂量

Mice: 30 mg/kg, 100 mg/kg^[1] (p.o.); 1 mg/kg^[1] (i.v.); 100 mg/kg^[3] (s.c.)

给药途径

p.o., i.v., s.c.

动物药代数据

Animal	Mice^[1]
Dose	1 mg/kg (i.v.) 30 mg/kg (p.o.)
Administration	i.v. p.o.
F	32% (p.o.)
T_1/2	1.3 h (i.v.)
T_max	0.4 h (p.o.)
CL	9.7 ml/min/kg (i.v.)
C_max	16.8 μM (p.o.)
Vd_ss	0.6 L/kg (i.v.)
AUC	3.46 μM·h (i.v.) 33.4 μM·h (p.o.)

参考文献

[1] Shultz MD, Cheung AK, et al. Identification of NVP-TNKS656: the use of structure-efficiency relationships to generate a highly potent, selective, and orally active tankyrase inhibitor. J Med Chem. 2013 Aug 22;56(16):6495-511.
[2] Schoumacher M, Hurov KE, et al. Inhibiting Tankyrases sensitizes KRAS-mutant cancer cells to MEK inhibitors via FGFR2 feedback signaling. Cancer Res. 2014 Jun 15;74(12):3294-305.
[3] Arqués O, Chicote I, et al. Tankyrase Inhibition Blocks Wnt/β-Catenin Pathway and Reverts Resistance to PI3K and AKT Inhibitors in the Treatment of Colorectal Cancer. Clin Cancer Res. 2016 Feb 1;22(3):644-56.

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
- 2.0219 mL
- 10.1095 mL
- 20.2191 mL
- 5 mM
- 0.4044 mL
- 2.0219 mL
- 4.0438 mL
- 10 mM
- 0.2022 mL
- 1.0110 mL
- 2.0219 mL

技术信息

CAS号

1419949-20-4

储存条件

粉末: Sealed in dry,Store in freezer, under -20°C

液体: -20°C:3-6 月 -80°C:12月

分子式

C27H34N4O5

运输

蓝冰

分子量

494.58

别名

TNKS656

溶解度

DMSO	105.0 mg/mL (212.3 mM)
Water	insoluble

动物实验配方

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