Discovery of 4-aryl-N-arylcarbonyl-2-aminothiazoles as Hec1/Nek2 inhibitors. Part I: optimization of in vitro potencies and pharmacokinetic properties.
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.
Development Center for Biotechnology , No. 101, Lane 169, Kangning Street, Xizhi District, New Taipei City 22180, Taiwan.
Ying-Shuan E
YS
Lee
Shih-Hsien
SH
Chuang
Lynn Y L
LY
Huang
Chun-Liang
CL
Lai
Yu-Hsiang
YH
Lin
Ju-Ying
JY
Yang
Chia-Wei
CW
Liu
Sheng-chuan
SC
Yang
Her-Sheng
HS
Lin
Chia-chi
CC
Chang
Jun-Yu
JY
Lai
Pei-Shiou
PS
Jian
King
K
Lam
Jia-Ming
JM
Chang
Johnson Y N
JY
Lau
Jiann-Jyh
JJ
Huang
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins; D055808:Drug Discovery; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D000072379:NIMA-Related Kinases; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D003598:Cytoskeletal Proteins; C120529:NDC80 protein, human; D009687:Nuclear Proteins; D013844:Thiazoles; C004483:2-aminothiazole; C089441:NEK2 protein, human; D000072379:NIMA-Related Kinases; D017346:Protein Serine-Threonine Kinases