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 towards the inhibition of MYC via the disruption of the protein-protein-interaction between MYC and its chromatin cofactor WDR5. 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 *

The Supporting Information is available free of charge on the ACS Publications website at DOI: • List of Fragment hits; pharmaceutical properties of select compounds; calculated physicochemical properties of selected compounds; histone methyl transferase assay data; X-ray data collection and refinement statistics; chemical structures of N.C and 30; experimental details for the synthesis of negative control.