WD40 repeat-containing protein 5 (WDR5) (WDR5)

WD40 repeat-containing protein 5 (WDR5) is a highly conserved scaffolding protein that serves as a critical structural component of several chromatin-modifying complexes, most notably the MLL/SET1 family of histone H3 lysine 4 (H3K4) methyltransferases [UniProt: P61964]. By facilitating the assembly of these complexes, WDR5 enables the trimethylation of H3K4, a key epigenetic mark associated with transcriptional activation and the maintenance of an open chromatin state [PubMed: 26838550]. Beyond its role in histone modification, WDR5 acts as an essential cofactor for the MYC oncoprotein, directly mediating MYC's recruitment to chromatin to drive the expression of genes involved in protein synthesis and cell cycle progression [PubMed: 25543138]. In various malignancies, particularly acute myeloid leukemia (AML) and certain solid tumors like breast and pancreatic cancer, WDR5 is often overexpressed and utilized to sustain oncogenic transcriptional programs [PubMed: 32156741]. Consequently, WDR5 has emerged as a high-priority therapeutic target, with drug discovery efforts focusing on small molecules that disrupt the WDR5-interacting (WIN) site or the WDR5-MYC interaction [PubMed: 31545166]. Inhibiting WDR5 leads to the downregulation of MYC-driven genes and the displacement of MLL complexes, resulting in potent anti-tumor activity in preclinical models [PubMed: 26308888].

Other names

WDR5BIG-3SWD3BMP2-induced gene 3 protein

Inhibition of the WDR5-interacting (WIN) site to disrupt MLL complex assembly and MYC recruitment to chromatin [PubMed: 31545166, PubMed: 25543138].