Abstract
The clinical success of multitargeted kinase inhibitors has stimulated efforts to identify promiscuous drugs with optimal selectivity profiles. It remains unclear to what extent such drugs can be rationally designed, particularly for combinations of targets that are structurally divergent. Here we report the systematic discovery of molecules that potently inhibit both tyrosine kinases and phosphatidylinositol-3-OH kinases, two protein families that are among the most intensely pursued cancer drug targets. Through iterative chemical synthesis, X-ray crystallography and kinome-level biochemical profiling, we identified compounds that inhibit a spectrum of new target combinations in these two families. Crystal structures revealed that the dual selectivity of these molecules is controlled by a hydrophobic pocket conserved in both enzyme classes and accessible through a rotatable bond in the drug skeleton. We show that one compound, PP121, blocks the proliferation of tumor cells by direct inhibition of oncogenic tyrosine kinases and phosphatidylinositol-3-OH kinases. These molecules demonstrate the feasibility of accessing a chemical space that intersects two families of oncogenes.
Publication types
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Comparative Study
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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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Amino Acid Sequence
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Blotting, Western
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Catalytic Domain / drug effects
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Cell Proliferation / drug effects
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Cells, Cultured
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Crystallography, X-Ray
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Drug Delivery Systems*
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Drug Design*
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Fusion Proteins, bcr-abl / antagonists & inhibitors
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Humans
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Inhibitory Concentration 50
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Models, Molecular
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Molecular Sequence Data
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Molecular Structure
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Phosphoinositide-3 Kinase Inhibitors*
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Protein Kinases / chemistry
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Protein Kinases / drug effects
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Protein Subunits / antagonists & inhibitors
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Pyrazoles / chemistry
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Pyrazoles / pharmacology*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology*
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Sequence Alignment
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Signal Transduction / drug effects
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TOR Serine-Threonine Kinases
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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PP121 compound
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Phosphoinositide-3 Kinase Inhibitors
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Protein Subunits
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Pyrazoles
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Pyrimidines
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Protein Kinases
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MTOR protein, human
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Protein-Tyrosine Kinases
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Fusion Proteins, bcr-abl
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TOR Serine-Threonine Kinases