Discovery and Optimization of Salicylic Acid-Derived Sulfonamide Inhibitors of the WD Repeat-Containing Protein 5–MYC Protein–Protein Interaction

The treatment of tumors driven by overexpression or amplification
of MYC oncogenes remains a significant challenge in drug discovery.
Here, we present a new strategy toward the inhibition of MYC via the
disruption of the protein–protein interaction between MYC and
its chromatin cofactor WD Repeat-Containing Protein 5. Blocking the
association of these proteins is hypothesized to disrupt the localization
of MYC to chromatin, thus disrupting the ability of MYC to sustain
tumorigenesis. Utilizing a high-throughput screening campaign and
subsequent structure-guided design, we identify small-molecule inhibitors
of this interaction with potent in vitro binding affinity and report
structurally related negative controls that can be used to study the
effect of this disruption. Our work suggests that disruption of this
protein–protein interaction may provide a path toward an effective
approach for the treatment of multiple tumors and anticipate that
the molecules disclosed can be used as starting points for future
efforts toward compounds with improved drug-like properties.