Abstract
A novel series of pyrazolobenzodiazepines 3 has been identified as potent inhibitors of cyclin-dependent kinase 2 (CDK2). Their synthesis and structure-activity relationships (SAR) are described. Representative compounds from this class reversibly inhibit CDK2 activity in vitro, and block cell cycle progression in human tumor cell lines. Further exploration has revealed that this class of compounds inhibits several kinases that play critical roles in cancer cell growth and division as well as tumor angiogenesis. Together, these properties suggest a compelling basis for their use as antitumor agents.
Copyright © 2010 Elsevier Ltd. All rights reserved.
MeSH terms
-
Animals
-
Antineoplastic Agents / chemical synthesis
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / pharmacology
-
Antineoplastic Agents / therapeutic use*
-
Benzodiazepines / chemical synthesis
-
Benzodiazepines / chemistry
-
Benzodiazepines / pharmacology
-
Benzodiazepines / therapeutic use*
-
Cell Cycle / drug effects
-
Cell Line, Tumor
-
Cyclin-Dependent Kinase 2 / antagonists & inhibitors*
-
Cyclin-Dependent Kinase 2 / metabolism
-
Humans
-
Inhibitory Concentration 50
-
Mice
-
Mice, Nude
-
Models, Molecular
-
Neoplasms / drug therapy*
-
Neovascularization, Pathologic / drug therapy
-
Protein Binding
-
Protein Kinase Inhibitors / chemical synthesis
-
Protein Kinase Inhibitors / chemistry
-
Protein Kinase Inhibitors / pharmacology
-
Protein Kinase Inhibitors / therapeutic use*
-
Pyrazoles / chemical synthesis
-
Pyrazoles / chemistry
-
Pyrazoles / pharmacology
-
Pyrazoles / therapeutic use
-
Structure-Activity Relationship
Substances
-
Antineoplastic Agents
-
Protein Kinase Inhibitors
-
Pyrazoles
-
Benzodiazepines
-
Cyclin-Dependent Kinase 2