Phthalazinone pyrazoles as potent, selective, and orally bioavailable inhibitors of Aurora-A kinase.
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.
Evotec (UK) Ltd., 114 Milton Park, Abingdon, UK. Michael.Prime@evotec.com
Michael E
ME
Prime
Stephen M
SM
Courtney
Frederick A
FA
Brookfield
Richard W
RW
Marston
Victoria
V
Walker
Justin
J
Warne
Andrew E
AE
Boyd
Norman A
NA
Kairies
Wolfgang
W
von der Saal
Anja
A
Limberg
Guy
G
Georges
Richard A
RA
Engh
Bernhard
B
Goller
Petra
P
Rueger
Matthias
M
Rueth
D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001682:Biological Availability; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010793:Phthalazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D010793:Phthalazines; D011720:Pyrazoles; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases