WDR5 WIN-site inhibitor

WDR5 WIN-site inhibitors are a class of small molecules designed to target the WD repeat-binding motif (WIN) site of the WD repeat-containing protein 5 (WDR5). WDR5 is a highly conserved scaffolding protein that is essential for the assembly and activity of several chromatin-modifying complexes, most notably the MLL/SET1 family of histone H3 lysine 4 (H3K4) methyltransferases. The WIN-site is a deep, hydrophobic pocket on the surface of WDR5 that mediates its interaction with the WIN motif found in proteins like MLL1. By competitively binding to this site, WIN-site inhibitors disrupt the interaction between WDR5 and MLL1, preventing the formation of the active WRAD complex (WDR5, RBBP5, ASH2L, and DPY30) and subsequently reducing H3K4 methylation levels. This epigenetic modulation leads to the downregulation of gene expression programs critical for cancer cell growth and survival, particularly in Myc-driven cancers such as glioblastoma and MLL-rearranged leukemias. While several small molecule WIN-site inhibitors have been developed as chemical probes and therapeutic candidates, their efficacy is often compared to other WDR5-targeting strategies, such as WBM-site inhibitors or proteolysis-targeting chimeras (PROTACs).

Other names

WDR5 WIN site inhibitorWDR-5 WIN site inhibitorWDR 5 WIN site inhibitorWDR5-MLL interaction inhibitorWDR-5-MLL interaction inhibitorWDR 5-MLL interaction inhibitor