期刊论文详细信息
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 卷:20
Structure-activity relationship study of acridine analogs as haspin and DYRK2 kinase inhibitors
Article
Cuny, Gregory D.1,2,3  Robin, Maxime4  Ulyanova, Natalia P.5,6  Patnaik, Debasis5,6  Pique, Valerie4  Casano, Gilles4  Liu, Ji-Feng7  Lin, Xiangjie7  Xian, Jun2,3  Glicksman, Marcie A.1,2,3  Stein, Ross L.1,2,3  Higgins, Jonathan M. G.5,6 
[1] Brigham & Womens Hosp, Lab Drug Discovery Neurodegenerat, Cambridge, MA 02139 USA
[2] Harvard Univ, Sch Med, Cambridge, MA 02139 USA
[3] Brigham & Womens Hosp, Partners Ctr Drug Discovery, Cambridge, MA 02139 USA
[4] Aix Marseille Univ, CNRS, iSm2, Ctr St Jerome,UMR 6263,Serv 552, F-13397 Marseille 20, France
[5] Brigham & Womens Hosp, Dept Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA
[6] Harvard Univ, Sch Med, Boston, MA 02115 USA
[7] Aberjona Labs Inc, Beverly, MA 01915 USA
关键词: Haspin;    DYRK2;    Kinase;    Inhibitor;    Oncology;    Structure-activity relationship;    Acridine;   
DOI  :  10.1016/j.bmcl.2010.04.150
来源: Elsevier
PDF
【 摘 要 】

Haspin is a serine/threonine kinase required for completion of normal mitosis that is highly expressed during cell proliferation, including in a number of neoplasms. Consequently, it has emerged as a potential therapeutic target in oncology. A high throughput screen of approximately 140,000 compounds identified an acridine analog as a potent haspin kinase inhibitor. Profiling against a panel of 270 kinases revealed that the compound also exhibited potent inhibitory activity for DYRK2, another serine/threonine kinase. An optimization study of the acridine series revealed that the structure-activity relationship (SAR) of the acridine series for haspin and DYRK2 inhibition had many similarities. However, several structural differences were noted that allowed generation of a potent haspin kinase inhibitor (33, IC(50) <60 nM) with 180fold selectivity over DYRK2. In addition, a moderately potent DYRK2 inhibitor (41, IC(50) <400 nM) with a 5.4-fold selectivity over haspin was also identified. (C) 2010 Elsevier Ltd. All rights reserved.

【 授权许可】

Free   

【 预 览 】
附件列表
Files Size Format View
10_1016_j_bmcl_2010_04_150.pdf 562KB PDF download
  文献评价指标  
  下载次数:1次 浏览次数:0次