8g3e
From Proteopedia
Crystal structure of human WDR5 in complex with (1M)-N-[(3,5-difluoro[1,1'-biphenyl]-4-yl)methyl]-6-methyl-4-oxo-1-(pyridin-3-yl)-1,4-dihydropyridazine-3-carboxamide (compound 2, WDR5-MYC inhibitor)
Structural highlights
FunctionWDR5_HUMAN Contributes to histone modification. May position the N-terminus of histone H3 for efficient trimethylation at 'Lys-4'. As part of the MLL1/MLL complex it is involved in methylation and dimethylation at 'Lys-4' of histone H3. H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues. May regulate osteoblasts differentiation.[1] [2] [3] [4] [5] Publication Abstract from PubMedWDR5 is a critical chromatin cofactor of MYC. WDR5 interacts with MYC through the WBM pocket and is hypothesized to anchor MYC to chromatin through its WIN site. Blocking the interaction of WDR5 and MYC impairs the recruitment of MYC to its target genes and disrupts the oncogenic function of MYC in cancer development, thus providing a promising strategy for the treatment of MYC-dysregulated cancers. Here, we describe the discovery of novel WDR5 WBM pocket antagonists containing a 1-phenyl dihydropyridazinone 3-carboxamide core that was identified from high-throughput screening and subsequent structure-based design. The leading compounds showed sub-micromolar inhibition in the biochemical assay. Among them, compound 12 can disrupt WDR5-MYC interaction in cells and reduce MYC target gene expression. Our work provides useful probes to study WDR5-MYC interaction and its function in cancers, which can also be used as the starting point for further optimization toward drug-like small molecules. Discovery and Structure-Based Design of Inhibitors of the WD Repeat-Containing Protein 5 (WDR5)-MYC Interaction.,Ding J, Liu L, Chiang YL, Zhao M, Liu H, Yang F, Shen L, Lin Y, Deng H, Gao J, Sage DR, West L, Llamas LA, Hao X, Kawatkar S, Li E, Jain RK, Tallarico JA, Canham SM, Wang H J Med Chem. 2023 Jun 22;66(12):8310-8323. doi: 10.1021/acs.jmedchem.3c00787. Epub , 2023 Jun 12. PMID:37307526[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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