6UJJ
Discovery of fragment-inspired heterocyclic benzenesulfonamides as inhibitors of the WDR5-MYC interaction
Summary for 6UJJ
| Entry DOI | 10.2210/pdb6ujj/pdb |
| Descriptor | WD repeat-containing protein 5, 5-[4-(trifluoromethyl)phenyl]-1H-tetrazole (3 entities in total) |
| Functional Keywords | wdr5, myc, structure-based design, fragment screening, transcription |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 34605.14 |
| Authors | Phan, J. (deposition date: 2019-10-03, 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 Cited by 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: 32223236DOI: 10.1021/acs.jmedchem.0c00224 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.731 Å) |
Structure validation
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