Abstract
The discovery of aurora kinases as essential regulators of cell division has led to intense interest in identifying small molecule aurora kinase inhibitors for the potential treatment of cancer. A high-throughput screening effort identified pyridinyl-pyrimidine 6a as a moderately potent dual inhibitor of aurora kinases -A and -B. Optimization of this hit resulted in an anthranilamide lead (6j) that possessed improved enzyme and cellular activity and exhibited a high level of kinase selectivity. However, this anthranilamide and subsequent analogues suffered from a lack of oral bioavailability. Converting the internally hydrogen-bonded six-membered pseudo-ring of the anthranilamide to a phthalazine (8a-b) led to a dramatic improvement in oral bioavailability (38-61%F) while maintaining the potency and selectivity characteristics of the anthranilamide series. In a COLO 205 tumor pharmacodynamic assay measuring phosphorylation of the aurora-B substrate histone H3 at serine 10 (p-histone H3), oral administration of 8b at 50 mg/kg demonstrated significant reduction in tumor p-histone H3 for at least 6 h.
MeSH terms
-
Administration, Oral
-
Animals
-
Antineoplastic Agents / chemical synthesis*
-
Antineoplastic Agents / pharmacokinetics
-
Antineoplastic Agents / pharmacology
-
Aurora Kinase B
-
Aurora Kinases
-
Biological Availability
-
Blood Proteins / metabolism
-
Cell Line, Tumor
-
Drug Screening Assays, Antitumor
-
Female
-
Histones / metabolism
-
Humans
-
In Vitro Techniques
-
Male
-
Mice
-
Mice, Nude
-
Microsomes, Liver / metabolism
-
Models, Molecular
-
Neoplasm Transplantation
-
Phthalazines / chemical synthesis*
-
Phthalazines / pharmacokinetics
-
Phthalazines / pharmacology
-
Protein Binding
-
Protein Serine-Threonine Kinases / antagonists & inhibitors*
-
Pyridines / chemical synthesis*
-
Pyridines / pharmacokinetics
-
Pyridines / pharmacology
-
Pyrimidines / chemical synthesis*
-
Pyrimidines / pharmacokinetics
-
Pyrimidines / pharmacology
-
Rats
-
Rats, Sprague-Dawley
-
Structure-Activity Relationship
-
Transplantation, Heterologous
Substances
-
4-(4-fluorophenyl)-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine
-
Antineoplastic Agents
-
Blood Proteins
-
Histones
-
Phthalazines
-
Pyridines
-
Pyrimidines
-
AURKB protein, human
-
Aurkb protein, mouse
-
Aurkb protein, rat
-
Aurora Kinase B
-
Aurora Kinases
-
Protein Serine-Threonine Kinases