Discovery of 4-Aryl-N-arylcarbonyl-2-aminothiazoles as Hec1/Nek2 Inhibitors. Part I: Optimization of in Vitro Potencies and Pharmacokinetic Properties

被引：39

作者：

Lee, Ying-Shuan E. ^{[1
]}

Chuang, Shih-Hsien ^{[1
]}

Huang, Lynn Y. L. ^{[2
]}

Lai, Chun-Liang ^{[1
]}

Lin, Yu-Hsiang ^{[1
]}

Yang, Ju-Ying ^{[1
]}

Liu, Chia-Wei ^{[1
]}

Yang, Sheng-chuan ^{[1
]}

Lin, Her-Sheng ^{[1
]}

Chang, Chia-chi ^{[2
]}

Lai, Jun-Yu ^{[3
]}

Jian, Pei-Shiou ^{[3
]}

Lam, King ^{[1
]}

Chang, Jia-Ming ^{[1
]}

Lau, Johnson Y. N. ^{[2
]}

Huang, Jiann-Jyh ^{[1
,3
]}

机构：

[1] Dev Ctr Biotechnol, New Taipei City 22180, Taiwan

[2] Taivex Therapeut Corp, Taipei 115, Taiwan

[3] Natl Chiayi Univ, Dept Appl Chem, Chiayi 60004, Taiwan

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 10期

关键词：

KINETOCHORE-MICROTUBULE ATTACHMENT; NDC80; COMPLEX; NEK2; KINASE; MITOTIC CHECKPOINT; HEC1; PROTEIN; CANCER; RECRUITMENT; BINDING; GROWTH;

D O I：

10.1021/jm401990s

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of 4-aryl-N-arylcarbonyl-2-aminothiazoles of scaffold 4 was designed and synthesized as Hec1/Nek2 inhibitors. Structural optimization of 4 led to compound S 32 bearing C-4' 4-methoxyphenoxy and 4-(o-fluoropyridyl)-carbonyl groups that showed low nanomolar in vitro antiproliferative activity (IC50: 16.3-42.7 nM), high intravenous AUC (64.9 mu M.h, 2.0 mg/kg) in SD rats, and significant in vivo antitumor activity (T/C = 32%, 20 mg/kg, IV) in mice bearing human MDA-MB-231 xenografts. Cell responses resulting from Hec1/Nek2 inhibition were observed in cells treated with 32, including a reduced level of Hec1 coimmunoprecipitated with Nek2, degradation of Nek2, mitotic abnormalities, and apoptosis. Compound 32 showed selectivity toward cancer cells over normal phenotype cells and was inactive in a [H-3]astemizole competitive binding assay for hERG liability screening. Therefore, 32 is as a good lead toward the discovery of a preclinical candidate targeting Hec1/Nek2 interaction.

引用

页码：4098 / 4110

页数：13

共 35 条

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