Abstract
A series of 2-amino-pyrazolopyridines was designed and synthesized as Polo-like kinase (Plk) inhibitors based on a low micromolar hit. The SAR was developed to provide compounds exhibiting low nanomolar inhibitory activity of Plk1; the phenotype of treated cells is consistent with Plk1 inhibition. A co-crystal structure of one of these compounds with zPlk1 confirms an ATP-competitive binding mode.
MeSH terms
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Adenosine Triphosphate / chemistry
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Amino Acid Motifs
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Cell Cycle
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Cell Cycle Proteins / antagonists & inhibitors*
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Chemistry, Pharmaceutical / methods*
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Crystallography, X-Ray
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Drug Design
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Humans
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Inhibitory Concentration 50
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Models, Chemical
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Molecular Conformation
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Phenotype
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Polo-Like Kinase 1
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrazoles / pharmacology
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Pyridines / chemical synthesis*
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Pyridines / chemistry
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Pyridines / pharmacology
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Structure-Activity Relationship
Substances
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Cell Cycle Proteins
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Proto-Oncogene Proteins
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Pyrazoles
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Pyridines
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pyrazolopyridine
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Adenosine Triphosphate
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Protein Serine-Threonine Kinases