313366-31-3Relevant academic research and scientific papers
Discovery of 4-aryl-N-arylcarbonyl-2-aminothiazoles as Hec1/Nek2 inhibitors. Part I: Optimization of in vitro potencies and pharmacokinetic properties
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
, p. 4098 - 4110 (2014/06/09)
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 [ 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.
