Abstract
A weak screening hit with suboptimal physicochemical properties was optimized against PFKFB3 kinase using critical structure-guided insights. The resulting compounds demonstrated high selectivity over related PFKFB isoforms and modulation of the target in a cellular context. A selected example demonstrated exposure in animals following oral dosing. Examples from this series may serve as useful probes to understand the emerging biology of this metabolic target.
MeSH terms
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Administration, Oral
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Animals
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Cell Line
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Drug Design*
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Humans
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Male
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Mice
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Models, Molecular
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Phosphofructokinase-2 / antagonists & inhibitors*
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Phosphofructokinase-2 / chemistry
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Phosphofructokinase-2 / metabolism*
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology*
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Rats, Wistar
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Structure-Activity Relationship
Substances
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Protein Kinase Inhibitors
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PFKFB3 protein, human
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Phosphofructokinase-2