Synthesis and SAR of inhibitors of protein kinase CK2: novel tricyclic quinoline analogs.

Abstract

Protein kinase CK2 is a potential drug target for many diseases including cancer and inflammation disorders. The crystal structure of clinical candidate CX-4945 1 with CK2 revealed an indirect interaction with the protein through hydrogen bonding between the NH of the 3-chlorophenyl amine and a water molecule. Herein, we investigate the relevance of this hydrogen bond by preparing several novel tricyclic derivatives lacking a NH moiety at the same position. This SAR study allowed the discovery of highly potent CK2 inhibitors.

• Authors: Mustapha Haddach, Fabrice Pierre, Collin F Regan, Cosmin Borsan, Jerome Michaux, Eric Stefan, Pauline Kerdoncuff, Michael K Schwaebe, Peter C Chua, Adam Siddiqui-Jain, Diwata Macalino, Denis Drygin, Sean E O'Brien, William G Rice, David M Ryckman
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 22 Issue 1 Pg. 45-8 (Jan 01 2012) ISSN: 1464-3405 [Electronic] England
• PMID: 22169261 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Quinolines
• Casein Kinase II

Topics

• Antineoplastic Agents (chemical synthesis, pharmacology)
• Casein Kinase II (antagonists & inhibitors, chemistry)
• Cell Line, Tumor
• Chemistry, Pharmaceutical (methods)
• Crystallography, X-Ray (methods)
• Drug Design
• Drug Screening Assays, Antitumor
• Humans
• Inhibitory Concentration 50
• Models, Chemical
• Models, Molecular
• Protein Conformation
• Quinolines (chemical synthesis, chemistry)
• Structure-Activity Relationship