Lee Ying-Shuan E, Chuang Shih-Hsien, Huang Lynn Y L, Lai Chun-Liang, Lin Yu-Hsiang, Yang Ju-Ying, Liu Chia-Wei, Yang Sheng-chuan, Lin Her-Sheng, Chang Chia-chi, Lai Jun-Yu, Jian Pei-Shiou, Lam King, Chang Jia-Ming, Lau Johnson Y N, Huang Jiann-Jyh
Development Center for Biotechnology , No. 101, Lane 169, Kangning Street, Xizhi District, New Taipei City 22180, Taiwan.
J Med Chem. 2014 May 22;57(10):4098-110. doi: 10.1021/jm401990s. Epub 2014 May 7.
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' 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 μM·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 [(3)H]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.
设计并合成了一系列具有4号骨架的4-芳基-N-芳基羰基-2-氨基噻唑作为Hec1/Nek2抑制剂。对4进行结构优化得到了化合物32，其带有C-4' 4-甲氧基苯氧基和4-(邻氟吡啶基)羰基，在体外显示出低纳摩尔的抗增殖活性（IC50：16.3 - 42.7 nM），在SD大鼠中具有高静脉血药浓度-时间曲线下面积（64.9 μM·h，2.0 mg/kg），并且在携带人MDA-MB-231异种移植瘤的小鼠中具有显著的体内抗肿瘤活性（T/C = 32%，20 mg/kg，静脉注射）。在用32处理的细胞中观察到了Hec1/Nek2抑制所导致的细胞反应，包括与Nek2共免疫沉淀的Hec1水平降低、Nek2降解、有丝分裂异常和细胞凋亡。化合物32对癌细胞的选择性高于正常表型细胞，并且在用于hERG安全性筛选的[(3)H]阿司咪唑竞争性结合试验中无活性。因此，32是发现靶向Hec1/Nek2相互作用的临床前候选药物的良好先导化合物。
