6u5m
Discovery and optimization of salicyclic acid-derived sulfonamide inhibitors of the WDR5:MYC protein-protein interaction
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 PubMedThe treatment of tumors driven by overexpression or amplification of MYC oncogenes remains a significant challenge in drug discovery. Here, we present a new strategy towards the inhibition of MYC via the disruption of the protein-protein-interaction between MYC and its chromatin cofactor WDR5. Blocking the association of these proteins is hypothesized to disrupt the localization of MYC to chromatin, thus disrupting the ability of MYC to sustain tumorigenesis. Utilizing a high-throughput screening campaign and subsequent structure-guided design, we identify small molecule inhibitors of this interaction with potent in vitro binding affinity, and report structurally related negative controls that can be used to study the effect of this disruption. Our work suggests that disruption of this protein-protein interaction may provide a path toward an effective approach for the treatment of multiple tumors, and anticipate that the molecules disclosed can be used as starting points for future efforts toward compounds with improved drug-like properties. Discovery and Optimization of Salicylic Acid-Derived Sulfonamide Inhibitors of the WD Repeat-Containing Protein 5 (WDR5)-MYC Protein-Protein Interaction.,Macdonald JD, Chacon Simon S, Han C, Wang F, Shaw JG, Howes JE, Sai J, Yuh J, Camper DV, Alicie BM, Alvarado J, Nikhar S, Payne WG, Aho ER, Bauer J, Zhao B, Phan J, Thomas LR, Rossanese OW, Tansey WP, Waterson AG, Stauffer SR, Fesik SW J Med Chem. 2019 Nov 14. doi: 10.1021/acs.jmedchem.9b01411. PMID:31724864[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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