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Reversible Linkage of Two Distinct Small Molecule Inhibitors of Myc Generates a Dimeric Inhibitor with Improved Potency That Is Active in Myc Over-Expressing Cancer Cell Lines
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Reversible Linkage of Two Distinct Small Molecule Inhibitors of Myc Generates a Dimeric Inhibitor with Improved Potency That Is Active in Myc Over-Expressing Cancer Cell Lines
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Reversible Linkage of Two Distinct Small Molecule Inhibitors of Myc Generates a Dimeric Inhibitor with Improved Potency That Is Active in Myc Over-Expressing Cancer Cell Lines
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Journal Article
Reversible Linkage of Two Distinct Small Molecule Inhibitors of Myc Generates a Dimeric Inhibitor with Improved Potency That Is Active in Myc Over-Expressing Cancer Cell Lines
2015
Overview
We describe the successful application of a novel approach for generating dimeric Myc inhibitors by modifying and reversibly linking two previously described small molecules. We synthesized two directed libraries of monomers, each comprised of a ligand, a connector, and a bioorthogonal linker element, to identify the optimal dimer configuration required to inhibit Myc. We identified combinations of monomers, termed self-assembling dimeric inhibitors, which displayed synergistic inhibition of Myc-dependent cell growth. We confirmed that these dimeric inhibitors directly bind to Myc blocking its interaction with Max and affect transcription of MYC dependent genes. Control combinations that are unable to form a dimer do not show any synergistic effects in these assays. Collectively, these data validate our new approach to generate more potent and selective inhibitors of Myc by self-assembly from smaller, lower affinity components. This approach provides an opportunity for developing novel therapeutics against Myc and other challenging protein:protein interaction (PPI) target classes.
Publisher
Public Library of Science,Public Library of Science (PLoS)
Subject
/ Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - biosynthesis
/ Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics
/ Cancer
/ Cell Proliferation - drug effects
/ Dimers
/ Gene Expression Regulation, Neoplastic - drug effects
/ Humans
/ Leukemia
/ Ligands
/ Monomers
/ Protein Interaction Maps - drug effects
/ Proteins
/ Proto-Oncogene Proteins c-myc - antagonists & inhibitors
/ Proto-Oncogene Proteins c-myc - biosynthesis
/ Proto-Oncogene Proteins c-myc - genetics
/ RNA, Messenger - biosynthesis
