1. Academic Validation
  2. Discovery of 4-aryl-N-arylcarbonyl-2-aminothiazoles as Hec1/Nek2 inhibitors. Part I: optimization of in vitro potencies and pharmacokinetic properties

Discovery of 4-aryl-N-arylcarbonyl-2-aminothiazoles as Hec1/Nek2 inhibitors. Part I: optimization of in vitro potencies and pharmacokinetic properties

  • J Med Chem. 2014 May 22;57(10):4098-110. doi: 10.1021/jm401990s.
Ying-Shuan E Lee 1 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
Affiliations

Affiliation

  • 1 Development Center for Biotechnology , No. 101, Lane 169, Kangning Street, Xizhi District, New Taipei City 22180, Taiwan.
Abstract

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.

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