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

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• 作者：Ying-Shuan E. Lee ; Shih-Hsien Chuang ; Lynn Y. L. Huang ; Chun-Liang Lai ; Yu-Hsiang Lin ; Ju-Ying Yang ; Chia-Wei Liu ; Sheng-chuan Yang ; Her-Sheng Lin ; Chia-chi Chang ; Jun-Yu Lai ; Pei-Shiou Jian ; King Lam ; Jia-Ming Chang ; Johnson Y. N. Lau ; Jiann-Jyh Huang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：May 22, 2014
• 年：2014
• 卷：57
• 期：10
• 页码：4098-4110
• 全文大小：570K
• 年卷期：v.57,no.10(May 22, 2014)
• ISSN：1520-4804

文摘

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 32 bearing C-4鈥?4-methoxyphenoxy and 4-(o-fluoropyridyl)carbonyl groups that showed low nanomolar in vitro antiproliferative activity (IC₅₀: 16.3鈥?2.7 nM), high intravenous AUC (64.9 渭M路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 [³H]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.