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


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.



haspin, DYRK2, inhibitor, oncology, structure-activity relationship, acridine


Copyright 2010 Bioorganic and Medicinal Chemistry Letters. This is a post-print version of a published paper that is available at: Recommended citation: Cuny, Gregory D., Maxime Robin, Natalia P. Ulyanova, Debasis Patnaik, Valerie Pique, Gilles Casano, Ji-Feng Liu et al. "Structure–activity relationship study of acridine analogs as haspin and DYRK2 kinase inhibitors." Bioorganic & medicinal chemistry letters 20, no. 12 (2010): 3491-3494. doi: 10.1016/j.bmcl.2010.04.150. This item has been deposited in accordance with publisher copyright and licensing terms and with author's permission.