ABSTRACT
Selective inhibitors of kinases that regulate the cell cycle, such as cyclin-dependent kinases (CDKs) and aurora kinases, could potentially become powerful tools for the treatment of cancer. We prepared and studied a series of 3,5,7-trisubstituted pyrazolo[4,3-d]pyrimidines, a new CDK inhibitor scaffold, to assess their CDK2 inhibitory and antiproliferative activities. A new compound, 2i, which preferentially inhibits CDK2, CDK5, and aurora A was identified. Both biochemical and cellular assays indicated that treatment with compound 2i caused the downregulation of cyclins A and B, the dephosphorylation of histone H3 at Ser10, and the induction of mitochondrial apoptosis in the HCT-116 colon cancer cell line. It also reduced migration as well as tube and lamellipodia formation in human endothelial cells. The kinase inhibitory profile of compound 2i suggests that its anti-angiogenic activity is linked to CDK5 inhibition. This dual mode of action involving apoptosis induction in cancer cells and the blocking of angiogenesis-like activity in endothelial cells offers possible therapeutic potential.
Subject(s)
Aurora Kinase A/antagonists & inhibitors , Cyclin-Dependent Kinase 2/antagonists & inhibitors , Cyclin-Dependent Kinase 5/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Angiogenesis Inhibitors/chemical synthesis , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Cycle/drug effects , Cyclin-Dependent Kinase Inhibitor Proteins/chemical synthesis , Cyclin-Dependent Kinase Inhibitor Proteins/chemistry , Cyclin-Dependent Kinase Inhibitor Proteins/pharmacology , Drug Design , Drug Screening Assays, Antitumor , HCT116 Cells , Human Umbilical Vein Endothelial Cells , Humans , Molecular Docking Simulation , Protein Kinase Inhibitors/chemical synthesis , Structure-Activity RelationshipABSTRACT
The bis-indole alkaloid indirubin and its analogues bear a very interesting natural pharmacophore. They are recognized mainly as kinase inhibitors, but several other activities make them possible candidates for preclinical studies. Based on the previously reported activity of 7-bromoindirubin-3'-oxime and its derivatives, the synthesis of indirubins bearing a heterocyclic nitrogen atom at position 7 was carried out. Herein, we report the first synthesis of 7-azaindirubin-3'-oxime (12) as well as its antiproliferative activity against 57 cancer cell lines and its inhibitory activity against a series of kinases. 7-Azaindirubin (10) and its 3'-oxime derivative (12) showed reduced activity as kinase inhibitors in comparison with other known indirubin derivatives, but antiproliferative activity with a best GI(50) value of 0.77 microM.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cyclin-Dependent Kinase Inhibitor Proteins/chemical synthesis , Cyclin-Dependent Kinase Inhibitor Proteins/pharmacology , Indole Alkaloids/chemical synthesis , Indole Alkaloids/pharmacology , Amino Acid Sequence , Antineoplastic Agents/chemistry , Cyclin-Dependent Kinase Inhibitor Proteins/chemistry , Drug Screening Assays, Antitumor , Female , Humans , Indole Alkaloids/chemistry , Indoles/pharmacology , Molecular StructureABSTRACT
The development of a novel series of imidazole pyrimidine amides as cyclin-dependent kinase (CDK) inhibitors is described. The series was found to have much improved CDK2 inhibition and potent in vitro anti-proliferative effects against cancer cell lines. Control of overall lipophilicity was important to achieve good in vitro potency along with acceptable physiochemical properties and margins against inhibition of both CYP isoforms and the hERG potassium ion channel. A compound with an attractive overall balance of properties was profiled in vivo and possessed suitable physiochemical and pharmacokinetic profiles for oral dosing.
Subject(s)
Cyclin-Dependent Kinase Inhibitor Proteins/chemical synthesis , Imidazoles/chemistry , Pyrimidines/chemistry , Administration, Oral , Animals , Cell Line, Tumor , Cyclin-Dependent Kinase Inhibitor Proteins/pharmacology , Drug Screening Assays, Antitumor , Female , Humans , Inhibitory Concentration 50 , Male , Mice , Mice, Nude , Rats , Rats, WistarABSTRACT
A series of four bicyclic cores were prepared and evaluated as cyclin-dependent kinase-2 (CDK2) inhibitors. From the in-vitro and cell-based analysis, the pyrazolo[1,5-a]pyrimidine core (represented by 9) emerged as the superior core for further elaboration in the identification of novel CDK2 inhibitors.
Subject(s)
Cyclin-Dependent Kinase 2/drug effects , Cyclin-Dependent Kinase Inhibitor Proteins/chemistry , Cyclin-Dependent Kinase Inhibitor Proteins/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Binding Sites , Crystallography, X-Ray , Cyclin-Dependent Kinase 2/chemistry , Cyclin-Dependent Kinase Inhibitor Proteins/chemical synthesis , Drug Design , Inhibitory Concentration 50 , Molecular Structure , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesisABSTRACT
A novel series of 3-hydroxychromones were prepared and found to be CDK inhibitors. Isothiazolidine 1,1-dioxide analogues showed potent CDK1 and CDK2 inhibitory activities and inhibited proliferation of EJ, HCT116, SW620, and MDAMB468 cancer cells.
