Structure–activity relationship study of beta-carboline derivatives as haspin kinase inhibitors


Haspin is a serine/threonine kinase that phosphorylates Thr-3 of histone H3 in mitosis that has emerged as a possible cancer therapeutic target. High throughput screening of approximately 140,000 compounds identified the beta-carbolines harmine and harmol as moderately potent haspin kinase inhibitors. Based on information obtained from a structure–activity relationship study previously conducted for an acridine series of haspin inhibitors in conjunction with in silico docking using a recently disclosed crystal structure of the kinase, harmine analogs were designed that resulted in significantly increased haspin kinase inhibitory potency. The harmine derivatives also demonstrated less activity towards DYRK2 compared to the acridine series. In vitro mouse liver microsome stability and kinase profiling of a representative member of the harmine series (42, LDN-211898) are also presented.



structure-activity relationship, beta-carboline, haspin, kinase, inhibitor


Copyright 2012 Bioorganic and Medicinal Chemistry Letters. This is a post-print version of a published paper that is available at: Recommended citation: Cuny, Gregory D., Natalia P. Ulyanova, Debasis Patnaik, Ji-Feng Liu, Xiangjie Lin, Ken Auerbach, Soumya S. Ray et al. "Structure–activity relationship study of beta-carboline derivatives as haspin kinase inhibitors." Bioorganic & medicinal chemistry letters 22, no. 5 (2012): 2015-2019. doi: 10.1016/j.bmcl.2012.01.028. This item has been deposited in accordance with publisher copyright and licensing and with the author's permission.