Abstract
The members of the Aurora kinase family play critical roles in the regulation of the cell cycle and mitotic spindle assembly and have been intensively investigated as potential targets for a new class of anticancer drugs. We describe a new highly potent and selective class of Aurora kinase inhibitors discovered using a phenotypic cellular screen. Optimized inhibitors display many of the hallmarks of Aurora inhibition including endoreduplication, polyploidy, and loss of cell viability in cancer cells. Structure-activity relationships with respect to kinome-wide selectivity and guided by an Aurora B co-crystal structure resulted in the identification of key selectivity determinants and discovery of a subseries with selectivity toward Aurora A. A direct comparison of biochemical and cellular profiles with respect to published Aurora inhibitors including VX-680, AZD1152, MLN8054, and a pyrimidine-based compound from Genentech demonstrates that compounds 1 and 3 will become valuable additional pharmacological probes of Aurora-dependent functions.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents, Phytogenic / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / chemistry
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Aurora Kinase B
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Aurora Kinases
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Benzazepines / pharmacology
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Cell Line, Tumor
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Cell Survival / drug effects
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Crystallography, X-Ray
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High-Throughput Screening Assays
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Humans
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Inhibitory Concentration 50
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / metabolism
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M Phase Cell Cycle Checkpoints / drug effects*
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Models, Molecular
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Organophosphates / pharmacology
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Paclitaxel / pharmacology
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Piperazines / pharmacology
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Pyrimidines / pharmacology
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Quinazolines / pharmacology
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Structure-Activity Relationship
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Xenopus laevis
Substances
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2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate
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Antineoplastic Agents, Phytogenic
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Benzazepines
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Isoenzymes
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MLN8054
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Organophosphates
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Piperazines
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Protein Kinase Inhibitors
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Pyrimidines
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Quinazolines
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tozasertib
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AURKB protein, human
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Aurora Kinase B
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Aurora Kinases
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Protein Serine-Threonine Kinases
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Paclitaxel