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Structure-activity relationship study of acridine analogs as haspin and DYRK2 kinase inhibitors.

Cuny G.D., Robin M., Ulyanova N.P., Patnaik D., Pique V., Casano G., Liu J.-F., Lin X., Xian J., Glicksman M.A., Stein R.L., Higgins J.M.G.

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 <60 nM) with 180-fold selectivity over DYRK2. In addition, a moderately potent DYRK2 inhibitor (41, IC50 <400 nM) with a 5.4-fold selectivity over haspin was also identified.

Bioorg. Med. Chem. Lett. 20:3491-3494(2010) [PubMed] [Europe PMC]

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