|1,1'-((((5-氯嘧啶-2,4-二基)双(氮烷二基))双(3-甲氧基-4,1-亚苯基))双(哌嗪-4,1-二基))双(乙-1-酮)|CsnPharm

CAS No.: 1472795-20-2

KRCA-0008 Catalog No. CSN17890

Synonyms: KRCA-0008

KRCA-0008 is a potent and selective ALK/Ack1 inhibitor with IC50 of 12 nM/4 nM for ALK and Ack1 respectively and displays drug-like properties without hERG liability.

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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Anaplastic lymphoma kinase (ALK) belongs to the insulin receptor superfamily of tyrosine kinase. ALK-fused genes such as NPMALK, EML4-ALK, KIF5-ALK are putative oncogenes and responsible for many cancers including anaplastic large-cell lymphomas (ALCL), inflammatory myofibroblastic tumors (IMT), diffuse large B cell lymphoma (DLBCL) and a variety of solid tumor types ^[2]. KRCA-0008 is selective and potent to ALK and Ack1 with IC50 of 12 nM, 4 nM respectively, and has drug-like properties without hERG concerns ^[3].KRCA-0008 has good water-solubility with moderate plasma protein binding (93% in rat) and low brain exposure (C_brain /C_plasma =~0.02). It has good liver microsomal stability (% remaining after 30 min: 52% in mouse, 89% in rat, 72% inhuman). It does not appear to cause hERG blockade (patch clamp IC50=30 μM) and is negative on Ames test (1000 μg/plate), chro-mosomal aberration assay and micronucleus assay. KRCA-0008 also shows promising pharmacokinetic parameters in both mice and rat (oral bioavailability = 66–94.5%). Finally, KRCA-0008 shows a modest tumor growth inhibition in vivo activity in H3122 human lung cancer bearing mice model comparable to Crizotinib without significant body weight change. The KRCA-0008 25 mpk and 50 mpk groups did not show dose-dependent tumor growth inhibition. ^[2].
作用机制Ligand interactions of KRCA-0008 display two hydrogen bonds with the backbone amide hydrogen and carbonyl oxygen of M1199 in the hinge region. The chlorine on the B-ring C5 position has hydrophobic interaction to L1196 as well as B-ring has CH/Π interaction with A1148 ^[4].

动物研究

剂量

Mice: 5 mg/kg^[1] (i.v.); 5 mg/kg^[1] (p.o.) Rat: 5 mg/kg^[1] (i.v.); 20 mg/kg^[1] (p.o.)

给药途径

i.v., p.o.

动物药代数据

Animal	Mice^[1]	Rats^[1]
Dose	5 mg/kg	5 mg/kg (i.v.) 20 mg/kg (p.o.)
Administration	i.v. or p.o.	i.v. p.o.
F	94.5% (p.o.)	66.2% (p.o.)
T_1/2	1.31 ± 0.381 h (i.v.) 2.23 ± 1.15 h (p.o.)	2.72 ± 0.903 h (i.v.) 2.19 ± 0.579 h (p.o.)
AUC_t	1.68 ± 0.23 μg·h/ml (i.v.) 1.59 ± 0.226 μg·h/ml (p.o.)	4.95 ± 1.15 μg·h/ml (i.v.) 13.1 ± 3.49 μg·h/ml (p.o.)
T_max	0.5 h (p.o.)	1.33 ± 0.578 h (p.o.)
CL	2.96 ± 0.438 L/kg/h (i.v.)	1.04 ± 0.216 L/kg/h (i.v.)
C_max	0.54 ± 0.174 μg/ml (p.o.)	2.51 ± 0.098 μg/ml (p.o.)
AUC_∞	1.72 ± 0.278 μg·h/ml (i.v.) 1.62 ± 0.23 μg·h/ml (p.o.)	4.95 ± 1.15 μg·h/ml (i.v.) 13.1 ± 3.52 μg·h/ml (p.o.)
Vss	4.352 ± 1.12 L/kg (i.v.)	1.504 ± 0.154 L/kg (i.v.)

参考文献

[1] Park CH, Choe H, et al. Novel bis-ortho-alkoxy-para-piperazinesubstituted-2,4-dianilinopyrimidines (KRCA-0008) as potent and selective ALK inhibitors for anticancer treatment. Bioorg Med Chem Lett. 2013 Nov 15;23(22):6192-6.
[2] Park CH. Novel bis-ortho-alkoxy-para-piperazinesubstituted-2,4-dianilinopyrimidines (KRCA-0008) as potent and selective ALK inhibitors for anticancer treatment. Bioorg Med Chem Lett. 2013 Nov 15;23(22):6192-6.
[3] Park CH. Novel bis-ortho-alkoxy-para-piperazinesubstituted-2,4-dianilinopyrimidines (KRCA-0008) as potent and selective ALK inhibitors for anticancer treatment. Bioorg Med Chem Lett. 2013 Nov 15;23(22):6192-6.
[4] Lee HJ. ALK inhibitors of bis-ortho-alkoxy-para-piperazinesubstituted-pyrimidines and -triazines for cancer treatment. Arch Pharm Res. 2014;37(9):1130-8.

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
- 1.6417 mL
- 8.2086 mL
- 16.4172 mL
- 5 mM
- 0.3283 mL
- 1.6417 mL
- 3.2834 mL
- 10 mM
- 0.1642 mL
- 0.8209 mL
- 1.6417 mL

技术信息

CAS号

1472795-20-2

储存条件

粉末: Keep in dark place,Inert atmosphere,2-8°C

液体: -20°C:3-6 月 -80°C:12月

分子式

C30H37ClN8O4

运输

蓝冰

分子量

609.12

别名

KRCA-0008

溶解度

DMSO	25.0 mg/mL (41.0 mM)

动物实验配方

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