Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 22, Issue 5, Pages 2015-2019Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2012.01.028
Keywords
Structure-activity relationship; Beta-carboline; Haspin; Kinase; Inhibitor
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Funding
- Partners Healthcare
- NIH [R01CA122608]
- Leukemia and Lymphoma Society
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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. (C) 2012 Elsevier Ltd. All rights reserved.
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