6UIK

Discovery of fragment-inspired heterocyclic benzenesulfonmides as inhibitors of the WDR5-MYC interaction

Summary for 6UIK

• Entry DOI: 10.2210/pdb6uik/pdb
• Descriptor: WD repeat domanin 5, 5-bromo-3-chloro-N-(1-cyclopentyl-1H-imidazol-4-yl)-2-hydroxybenzene-1-sulfonamide (3 entities in total)
• Functional Keywords: wdr5, myc, structure-based design, fragment screening, transcription
• Biological source: Homo sapiens
• Total number of polymer chains: 2
• Total formula weight: 67825.46

Authors

Zhao, B. (deposition date: 2019-10-01, release date: 2020-04-15, Last modification date: 2023-10-11)

Primary citation

Chacon Simon, S.,Wang, F.,Thomas, L.R.,Phan, J.,Zhao, B.,Olejniczak, E.T.,Macdonald, J.D.,Shaw, J.G.,Schlund, C.,Payne, W.,Creighton, J.,Stauffer, S.R.,Waterson, A.G.,Tansey, W.P.,Fesik, S.W.
Discovery of WD Repeat-Containing Protein 5 (WDR5)-MYC Inhibitors Using Fragment-Based Methods and Structure-Based Design.
J.Med.Chem., 63:4315-4333, 2020

PubMed Abstract: The frequent deregulation of MYC and its elevated expression via multiple mechanisms drives cells to a tumorigenic state. Indeed, MYC is overexpressed in up to ∼50% of human cancers and is considered a highly validated anticancer target. Recently, we discovered that WD repeat-containing protein 5 (WDR5) binds to MYC and is a critical cofactor required for the recruitment of MYC to its target genes and reported the first small molecule inhibitors of the WDR5-MYC interaction using structure-based design. These compounds display high binding affinity, but have poor physicochemical properties and are hence not suitable for studies. Herein, we conducted an NMR-based fragment screening to identify additional chemical matter and, using a structure-based approach, we merged a fragment hit with the previously reported sulfonamide series. Compounds in this series can disrupt the WDR5-MYC interaction in cells, and as a consequence, we observed a reduction of MYC localization to chromatin.

PubMed: 32223236
DOI: 10.1021/acs.jmedchem.0c00224

Experimental method

X-RAY DIFFRACTION (1.6 Å)