Abstract
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.
Highlights
The use of small molecules as drugs to inhibit cancer targets has made tremendous strides over the last 20 years, with numerous drugs in routine clinical use in a wide range of different cancers
We demonstrate that our new inhibitors directly bind to Myc with improved affinity over the existing small molecule inhibitors, disrupt the Myc:Max interaction in vitro, and impact expression of MYC regulated genes in cells resulting in anti-proliferative effects in Myc-expressing tumor cell lines
Extensive research has been carried out on Myc’s biological function clearly demonstrating its important role in tumor biology, but no approaches have yet resulted in the successful development of therapeutics that directly target Myc
Summary
The use of small molecules as drugs to inhibit cancer targets has made tremendous strides over the last 20 years, with numerous drugs in routine clinical use in a wide range of different cancers. This approach has been successful for enzymatic targets, where the binding site is a well-defined, distinct pocket in the protein that lends itself to the rational design of highly potent inhibitors. Efforts to expand the use of small molecules to target larger.
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