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Discovery of WD Repeat-Containing Protein 5 (WDR5)-MYC Inhibitors Using Fragment-Based Methods and Structure-Based
Selena Chacón Simon, Feng Wang, Lance R Thomas
1Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
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 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.
Insights
Researchers developed new compounds to inhibit the MYC-WDR5 interaction, a key driver of cancer. These novel inhibitors reduce MYC
Area of Science:
- Oncology
- Molecular Biology
- Medicinal Chemistry
Background:
- MYC deregulation is a frequent driver of tumorigenesis, making it a validated anticancer target.
- The WD repeat-containing protein 5 (WDR5) acts as a critical cofactor, mediating MYC recruitment to target genes.
- Previous small molecule inhibitors of the WDR5-MYC interaction showed promise but lacked suitable in vivo properties.
Purpose of the Study:
- To identify novel chemical matter targeting the WDR5-MYC interaction.
- To develop improved inhibitors with better drug-like properties for potential in vivo application.
- To validate the disruption of the WDR5-MYC interaction in a cellular context.
Main Methods:
- NMR-based fragment screening was employed to discover new binding fragments.
- Structure-based drug design was used to merge fragment hits with existing chemical series.
- The WDR5-MYC interaction and MYC localization to chromatin were assessed in cellular assays.
Main Results:
- A novel series of compounds was generated by merging a fragment hit with a sulfonamide series.
- These compounds effectively disrupt the WDR5-MYC interaction within cells.
- A significant reduction in MYC's localization to chromatin was observed as a consequence of WDR5-MYC inhibition.
Conclusions:
- Novel small molecules capable of disrupting the WDR5-MYC interaction have been developed.
- These compounds demonstrate potential for targeting MYC-driven cancers.
- Further optimization may lead to viable therapeutic agents for in vivo studies.
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