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.
Subject(s)
Antineoplastic Agents/therapeutic use , Benzodiazepines/therapeutic use , Cyclin-Dependent Kinase 2/antagonists & inhibitors , Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzodiazepines/chemical synthesis , Benzodiazepines/chemistry , Benzodiazepines/pharmacology , Cell Cycle/drug effects , Cell Line, Tumor , Cyclin-Dependent Kinase 2/metabolism , Humans , Inhibitory Concentration 50 , Mice , Mice, Nude , Models, Molecular , Neovascularization, Pathologic/drug therapy , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Structure-Activity RelationshipABSTRACT
A novel series of quinolinyl-methylene-thiazolinones has been identified as potent and selective cyclin-dependent kinase 1 (CDK1) inhibitors. Their synthesis and structure activity relationships (SAR) are described. Representative compounds from this class reversibly inhibit CDK1 activity in vitro, and block cell cycle progression in human tumor cell lines, suggesting a potential use as antitumor agents.
Subject(s)
CDC2 Protein Kinase/antagonists & inhibitors , Thiazoles/chemical synthesis , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Structure-Activity Relationship , Thiazoles/pharmacologyABSTRACT
RO4396686 is a small molecule KDR, FGFR, and PDGFR inhibitor with good pharmacokinetic properties in rodents. In a mouse corneal neovascularization assay, this compound inhibited VEGF-induced angiogenesis. Tested in a H460a xenograft tumor model this agent effected significant tumor growth inhibition at doses as low as 50mg/kg.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Neoplasms, Experimental/blood supply , Neovascularization, Pathologic , Pyrimidines/pharmacology , Angiogenesis Inhibitors/chemistry , Animals , Mice , Mice, Nude , Rats , Rats, Wistar , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors , Vascular Endothelial Growth Factor A/physiology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitorsABSTRACT
A novel class of 3,5,6-trisubstituted naphthostyril analogues was designed and synthesized to study the structure-activity relationship for inhibition of cyclin-dependent kinase 2 (CDK2). These compounds, particularly molecules with side-chain modifications providing additional hydrogen bonding capability, were demonstrated to be potent CDK2 inhibitors with cellular activities consistent with CDK2 inhibition. These molecules inhibited tumor cell proliferation and G1-S and G2-M cell-cycle progression in vitro. The X-ray crystal structure of a 2-aminoethyleneamine derivative bound to CDK2, refined to 2.5A resolution, is presented.
