Abstract
Pyrazolopyrimidines with potent antiproliferative properties were developed by an adaptive strategy that applies ligand-based design and phenotypic screening iteratively and is informed by biochemical assays. To drive development toward specific oncopathways, compounds were tested against cancer cells that overexpress, or not, AXL kinase. Identified phenotypic hits were found to inhibit oncotargets AXL, RET, and FLT3. Subsequent optimization generated antiproliferative lead compounds with unique selectivity profiles, including selective AXL inhibitors and a highly potent inhibitor of FLT3.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents
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Axl Receptor Tyrosine Kinase
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Cell Line, Tumor
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Cell Survival
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Drug Design
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Drug Evaluation, Preclinical
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Humans
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Ligands
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins / antagonists & inhibitors
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Pyrazoles / chemistry
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Pyrimidines / chemistry
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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fms-Like Tyrosine Kinase 3 / antagonists & inhibitors
Substances
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Antineoplastic Agents
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Ligands
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Pyrazoles
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Pyrimidines
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pyrazolylpyrimidine
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Receptor Protein-Tyrosine Kinases
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fms-Like Tyrosine Kinase 3
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Axl Receptor Tyrosine Kinase
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AXL protein, human