Abstract
The rational design of inhibitors of the bHLH-ZIP oncoprotein c-Myc is hampered by a lack of structure in its monomeric state. We describe herein the design of novel, low-molecular-weight, synthetic α-helix mimetics that recognize helical c-Myc in its transcriptionally active coiled-coil structure in association with its obligate bHLH-ZIP partner Max. These compounds perturb the heterodimer's binding to its canonical E-box DNA sequence without causing protein-protein dissociation, heralding a new mechanistic class of "direct" c-Myc inhibitors. In addition to electrophoretic mobility shift assays, this model was corroborated by further biophysical methods, including NMR spectroscopy and surface plasmon resonance. Several compounds demonstrated a 2-fold or greater selectivity for c-Myc-Max heterodimers over Max-Max homodimers with IC50 values as low as 5.6 μM. Finally, these compounds inhibited the proliferation of c-Myc-expressing cell lines in a concentration-dependent manner that correlated with the loss of expression of a c-Myc-dependent reporter plasmid despite the fact that c-Myc-Max heterodimers remained intact.
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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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacology*
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / chemistry*
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
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Cell Cycle Checkpoints / drug effects
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Cell Line, Tumor / drug effects
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Cell Proliferation / drug effects
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Chemistry Techniques, Synthetic
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Dose-Response Relationship, Drug
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Drug Design
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Drug Evaluation, Preclinical / methods
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Electrophoretic Mobility Shift Assay
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Helix-Loop-Helix Motifs
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Humans
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Inhibitory Concentration 50
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Molecular Mimicry
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Nuclear Magnetic Resonance, Biomolecular
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Protein Multimerization
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Proto-Oncogene Proteins c-myc / antagonists & inhibitors*
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Proto-Oncogene Proteins c-myc / chemistry
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Proto-Oncogene Proteins c-myc / metabolism
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology
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Surface Plasmon Resonance
Substances
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Antineoplastic Agents
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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MAX protein, human
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Proto-Oncogene Proteins c-myc
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Small Molecule Libraries