Structure-based design and synthesis of novel macrocyclic pyrazolo[1,5-a] [1,3,5]triazine compounds as potent inhibitors of protein kinase CK2 and their anticancer activities

Zhe Nie; Carin Perretta; Philip Erickson; Stephen Margosiak; Jia Lu; April Averill; Robert Almassy; Shaosong Chu

doi:10.1016/j.bmcl.2007.11.074

Structure-based design and synthesis of novel macrocyclic pyrazolo[1,5-a] [1,3,5]triazine compounds as potent inhibitors of protein kinase CK2 and their anticancer activities

Bioorg Med Chem Lett. 2008 Jan 15;18(2):619-23. doi: 10.1016/j.bmcl.2007.11.074. Epub 2007 Nov 28.

Authors

Zhe Nie¹, Carin Perretta, Philip Erickson, Stephen Margosiak, Jia Lu, April Averill, Robert Almassy, Shaosong Chu

Affiliation

¹ Department of Medicinal Chemistry, Polaris Pharmaceuticals Inc., San Diego, CA 92121, USA. zhe.nie@takedasd.com

PMID: 18055206
DOI: 10.1016/j.bmcl.2007.11.074

Abstract

A series of macrocyclic derivatives has been designed and synthesized based on the X-ray co-crystal structures of pyrazolo[1,5-a] [1,3,5]triazines with corn CK2 (cCK2) protein. Bioassays demonstrated that these macrocyclic pyrazolo[1,5-a] [1,3,5]triazine compounds are potent CK2 inhibitors with K(i) around 1.0 nM and strongly inhibit cancer cell growth with IC(50) as low as approximately 100 nM.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Casein Kinase II / antagonists & inhibitors*
Cell Line, Tumor
Colonic Neoplasms / pathology
Crystallography, X-Ray
Drug Design
Humans
Male
Molecular Conformation
Prostatic Neoplasms / pathology
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
Triazines / chemical synthesis
Triazines / chemistry*
Triazines / pharmacology*

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Triazines
Casein Kinase II