Development of o-chlorophenyl substituted pyrimidines as exceptionally potent aurora kinase inhibitors.
The o-carboxylic acid substituted bisanilinopyrimidine 1 was identified as a potent hit (Aurora A IC(50) = 6.1 ± 1.0 nM) from in-house screening. Detailed structure-activity relationship (SAR) studies indicated that polar substituents at the para position of the B-ring are critical for potent activity. X-ray crystallography studies revealed that compound 1 is a type I inhibitor that binds the Aurora kinase active site in a DFG-in conformation. Structure-activity guided replacement of the A-ring carboxylic acid with halogens and incorporation of fluorine at the pyrimidine 5-position led to highly potent inhibitors of Aurora A that bind in a DFG-out conformation. B-Ring modifications were undertaken to improve the solubility and cell permeability. Compounds such as 9m with water-solubilizing moieties at the para position of the B-ring inhibited the autophosphorylation of Aurora A in MDA-MB-468 breast cancer cells.
Department of Drug Discovery, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.|Department of Chemical Biology Core, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.|Department of Oncologic Sciences, University of South Florida, Tampa, FL 33620, USA.
Harshani R
HR
Lawrence
Department of Drug Discovery, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Matthew P
MP
Martin
Department of Chemical Biology Core, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Yunting
Y
Luo
Department of Drug Discovery, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Roberta
R
Pireddu
Department of Drug Discovery, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Hua
H
Yang
Department of Drug Discovery, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Harsukh
H
Gevariya
Department of Drug Discovery, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Sevil
S
Ozcan
Department of Drug Discovery, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Jin-Yi
JY
Zhu
Department of Chemical Biology Core, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Robert
R
Kendig
Department of Chemical Biology Core, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.|Department of Drug Discovery, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Mercedes
M
Rodriguez
Department of Drug Discovery, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Roy
R
Elias
Department of Molecular Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.|Department of Oncologic Sciences, University of South Florida, Tampa, FL 33620, USA.
Jin Q
JQ
Cheng
Department of Drug Discovery, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.|Department of Oncologic Sciences, University of South Florida, Tampa, FL 33620, USA.|Department of Molecular Medicine, University of South Florida, Tampa, FL 33620, USA.
Saïd M
SM
Sebti
Department of Drug Discovery, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.|Department of Chemical Biology Core, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.|Department of Oncologic Sciences, University of South Florida, Tampa, FL 33620, USA.
Ernst
E
Schonbrunn
Department of Drug Discovery, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.|Department of Oncologic Sciences, University of South Florida, Tampa, FL 33620, USA.
Nicholas J
NJ
Lawrence
D064127:Aurora Kinases; D018360:Crystallography, X-Ray; D057166:High-Throughput Screening Assays; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases