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

Abstract

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.

• Authors: Gregory D Cuny, Natalia P Ulyanova, Debasis Patnaik, Ji-Feng Liu, Xiangjie Lin, Ken Auerbach, Soumya S Ray, Jun Xian, Marcie A Glicksman, Ross L Stein, Jonathan M G Higgins
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 22 Issue 5 Pg. 2015-9 (Mar 01 2012) ISSN: 1464-3405 [Electronic] England
• PMID: 22335895 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Carbolines
• Intracellular Signaling Peptides and Proteins
• Protein Kinase Inhibitors
• Protein-Tyrosine Kinases
• HASPIN protein, human
• Protein Serine-Threonine Kinases

Topics

• Animals
• Carbolines (chemistry, metabolism, pharmacology)
• Humans
• Intracellular Signaling Peptides and Proteins (antagonists & inhibitors, metabolism)
• Mice
• Microsomes, Liver (metabolism)
• Models, Molecular
• Protein Kinase Inhibitors (chemistry, metabolism, pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship
• Dyrk Kinases