Abstract
The inhibition of Aurora kinases in order to arrest mitosis and subsequently inhibit tumor growth via apoptosis of proliferating cells has generated significant discussion within the literature. We report a novel class of Aurora kinase inhibitors based upon a phthalazinone pyrazole scaffold. The development of the phthalazinone template resulted in a potent Aurora-A selective series of compounds (typically >1000-fold selectivity over Aurora-B) that display good pharmacological profiles with significantly improved oral bioavailability compared to the well studied Aurora inhibitor VX-680.
MeSH terms
-
Administration, Oral
-
Antineoplastic Agents / chemical synthesis*
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / pharmacology
-
Aurora Kinase B
-
Aurora Kinases
-
Biological Availability
-
Cell Line, Tumor
-
Crystallography, X-Ray
-
Drug Screening Assays, Antitumor
-
Humans
-
Models, Molecular
-
Molecular Structure
-
Phthalazines / chemical synthesis*
-
Phthalazines / chemistry
-
Phthalazines / pharmacology
-
Protein Serine-Threonine Kinases / antagonists & inhibitors*
-
Pyrazoles / chemical synthesis*
-
Pyrazoles / chemistry
-
Pyrazoles / pharmacology
-
Structure-Activity Relationship
Substances
-
Antineoplastic Agents
-
Phthalazines
-
Pyrazoles
-
AURKB protein, human
-
Aurora Kinase B
-
Aurora Kinases
-
Protein Serine-Threonine Kinases