Discovery of WD Repeat-Containing Protein 5 (WDR5)–MYC Inhibitors Using Fragment-Based Methods and Structure-Based Design
| Autor: | William G. Payne, Caden Schlund, Feng Wang, Joy Creighton, William P. Tansey, Jonathan David Macdonald, Edward T. Olejniczak, Jason Phan, Alex G. Waterson, Shaun R. Stauffer, Bin Zhao, J. Grace Shaw, Selena Chacón Simon, Lance R. Thomas, Stephen W. Fesik |
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| Rok vydání: | 2020 |
| Předmět: |
Sulfonamides
Chemistry WD Repeat-Containing Protein 5 HEK 293 cells Intracellular Signaling Peptides and Proteins Small molecule Article Protein Structure Tertiary Cell biology Chromatin Proto-Oncogene Proteins c-myc Structure-Activity Relationship HEK293 Cells Protein structure Cell Line Tumor Drug Design Drug Discovery Humans Molecular Medicine Structure–activity relationship WDR5 Gene |
| Zdroj: | Journal of Medicinal Chemistry. 63:4315-4333 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.0c00224 |
| Popis: | 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 in vivo 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. |
| Databáze: | OpenAIRE |
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