WD repeat-containing protein 5–MYC proto-oncogene protein interaction (WDR5–MYC PPI)

The WD repeat-containing protein 5 (WDR5)–MYC proto-oncogene protein interaction is a critical regulatory node in the transcriptional program of MYC-driven cancers (Thomas et al., 2015, Nature). WDR5 acts as a scaffold that facilitates the recruitment of MYC to its target gene promoters, particularly those involved in protein synthesis and biomass accumulation (Bryan et al., 2020, Trends in Cancer). By binding to the WDR5-binding motif (WBM) of MYC, WDR5 stabilizes MYC on chromatin, which is essential for its oncogenic activity. Disrupting this protein-protein interaction (PPI) with small molecules like OICR-9429 has emerged as a promising strategy to indirectly inhibit MYC, which has long been considered undruggable due to its lack of a defined small-molecule binding pocket (Grebien et al., 2015, Nature Chemical Biology). Preclinical studies have shown that inhibiting this interaction leads to the displacement of MYC from chromatin and reduced expression of MYC-target genes (Wang et al., 2015, JBC). However, therapeutic development must carefully manage potential off-target effects on other WDR5-dependent complexes, such as the MLL/SET histone methyltransferase complexes, and the systemic impact of MYC inhibition on normal regenerative tissues (Aho et al., 2019, Cell Reports).

Other names

WDR5-c-Myc interactionWDR5-MYC complexWDR5-MYC bindingWDR5-MYC interface

Small molecule inhibition of the WDR5-binding motif (WBM) on MYC to prevent its recruitment to chromatin and subsequent transcriptional activation of oncogenic target genes.