Discovery of WD Repeat-Containing Protein 5 (WDR5)–MYC Inhibitors Using Fragment-Based Methods and Structure-Based Design

The frequent deregulation of MYC and its elevated expression via
multiple mechanisms drives cells to a tumorigenic state. Indeed, MYC
is overexpressed in up to ∼50% of human cancers and is considered
a highly validated anticancer target. Recently, we discovered that
WD repeat-containing protein 5 (WDR5) binds to MYC and is a critical
cofactor required for the recruitment of MYC to its target genes and
reported the first small molecule inhibitors of the WDR5–MYC
interaction using structure-based design. These compounds display
high binding affinity, but have poor physicochemical properties and
are hence not suitable for in vivo studies. Herein,
we conducted an NMR-based fragment screening to identify additional
chemical matter and, using a structure-based approach, we merged a
fragment hit with the previously reported sulfonamide series. Compounds
in this series can disrupt the WDR5–MYC interaction in cells,
and as a consequence, we observed a reduction of MYC localization
to chromatin.