6dak
From Proteopedia
Discovery of Potent 2-Aryl-6,7-Dihydro-5HPyrrolo[ 1,2-a]imidazoles as WDR5 WIN-site Inhibitors Using Fragment-Based Methods and Structure-Based Design
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 chromatin-regulatory scaffold protein overexpressed in various cancers and a potential epigenetic drug target for the treatment of mixed-lineage leukemia. Here, we describe the discovery of potent and selective WDR5-WIN-site inhibitors using fragment-based methods and structure-based design. NMR-based screening of a large fragment library identified several chemically distinct hit series that bind to the WIN site within WDR5. Members of a 6,7-dihydro-5 H-pyrrolo[1,2- a]imidazole fragment class were expanded using a structure-based design approach to arrive at lead compounds with dissociation constants <10 nM and micromolar cellular activity against an AML-leukemia cell line. These compounds represent starting points for the discovery of clinically useful WDR5 inhibitors for the treatment of cancer. Discovery of Potent 2-Aryl-6,7-dihydro-5 H-pyrrolo[1,2- a]imidazoles as WDR5-WIN-Site Inhibitors Using Fragment-Based Methods and Structure-Based Design.,Wang F, Jeon KO, Salovich JM, Macdonald JD, Alvarado J, Gogliotti RD, Phan J, Olejniczak ET, Sun Q, Wang S, Camper D, Yuh JP, Shaw JG, Sai J, Rossanese OW, Tansey WP, Stauffer SR, Fesik SW J Med Chem. 2018 Jul 12;61(13):5623-5642. doi: 10.1021/acs.jmedchem.8b00375. Epub, 2018 Jun 29. PMID:29889518[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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