6ucs
From Proteopedia
Discovery and Structure-Based optimization of potent and selective WDR5 inhibitors containing a dihydroisoquinolinone bicyclic core
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 PubMedWD repeat domain 5 (WDR5) is a member of the WD40-repeat protein family that plays a critical role in multiple chromatin-centric processes. Overexpression of WDR5 correlates with poor clinical outcome in many human cancers, and WDR5 itself has emerged as an attractive target for therapy. Most drug-discovery efforts center on the WIN site of WDR5 that is responsible for recruitment of WDR5 to chromatin. Here, we describe discovery of a novel WDR5 WIN site antagonists containing a dihydroisoquinolinone bicyclic core using structure-based design. These compounds exhibit picomolar binding affinity and selective concentration-dependent anti-proliferative activities in sensitive MLL-fusion cell lines. Furthermore, these WDR5 WIN site binders inhibit proliferation in MYC-driven cancer cells and reduce MYC recruitment to chromatin at MYC/WDR5 co-bound genes. Thus, these molecules are useful probes to study the implication of WDR5 inhibition in cancers and serve as a potential starting point toward the discovery of anti-WDR5 therapeutics. Discovery and Structure-Based Optimization of Potent and Selective WD repeat domain 5 (WDR5) Inhibitors Containing a Dihydroisoquinolinone Bicyclic Core.,Tian J, Teuscher K, Aho ER, Alvarado JR, Mills JJ, Meyers KM, Gogliotti RD, Han C, Macdonald JD, Sai J, Shaw JG, Sensintaffar JL, Zhao B, Rietz TA, Thomas LR, Payne WG, Moore WJ, Stott GM, Kondo J, Inoue M, Coffey R, Tansey WP, Stauffer S, Lee T, Fesik SW J Med Chem. 2019 Dec 20. doi: 10.1021/acs.jmedchem.9b01608. PMID:31858797[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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