Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10588777 | Bioorganic & Medicinal Chemistry Letters | 2010 | 4 Pages |
Abstract
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, IC50 <60Â nM) with 180-fold selectivity over DYRK2. In addition, a moderately potent DYRK2 inhibitor (41, IC50 <400Â nM) with a 5.4-fold selectivity over haspin was also identified.
Related Topics
Physical Sciences and Engineering
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Authors
Gregory D. Cuny, Maxime Robin, Natalia P. Ulyanova, Debasis Patnaik, Valerie Pique, Gilles Casano, Ji-Feng Liu, Xiangjie Lin, Jun Xian, Marcie A. Glicksman, Ross L. Stein, Jonathan M.G. Higgins,