WD repeat-containing protein 5 (WDR5) (WDR5)

WD repeat-containing protein 5 (WDR5) is a highly conserved scaffold protein that plays a critical role in the assembly and activity of several epigenetic regulatory complexes, most notably the MLL/SET1 family of histone H3 lysine 4 (H3K4) methyltransferases (UniProt P61964). The WIN (WDR5-interacting network) motif binding site on WDR5 is a deep, druggable pocket that mediates its interaction with the MLL1 catalytic unit and other proteins (Alicea-Velázquez et al., 2016). By acting as a bridge within the WRAD complex, WDR5 facilitates the transition of MLL1 from a mono-methyltransferase to a di- and tri-methyltransferase, which is essential for active gene transcription (UniProt P61964). In the context of disease, WDR5 is frequently overexpressed or hijacked in various cancers, particularly MLL-rearranged leukemias and MYC-driven malignancies, where it maintains the expression of oncogenic programs (Grebien et al., 2015; Thomas et al., 2015). Small molecule inhibitors targeting the WIN site disrupt these protein-protein interactions, leading to the disassembly of the methyltransferase complex or the displacement of oncogenic transcription factors like MYC from chromatin (Thomas et al., 2015; Guarnaccia et al., 2021). This targeted disruption results in decreased H3K4 methylation at specific loci, induction of cell cycle arrest, and apoptosis in sensitive cancer cells (Grebien et al., 2015). Consequently, the WDR5 WIN site has emerged as a high-priority therapeutic target for the development of novel epigenetic inhibitors in oncology (Guarnaccia et al., 2021).

Other names

WDR5WD repeat-containing protein 5BIG-3SWD3

Inhibition of protein-protein interaction (PPI) at the WIN motif binding site; Disruption of the MLL/SET1 methyltransferase complex; Displacement of MYC from chromatin; Reduction of H3K4me3 levels