Discovery of WD Repeat-Containing Protein 5 (WDR5)-MYC Inhibitors Using Fragment-Based Methods and Structure-Based Design

Article abstract of DOI:10.1021/acs.jmedchem.0c00224

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.

Full text of DOI:10.1021/acs.jmedchem.0c00224

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Article
Discovery of WD Repeat-Containing Protein 5 (WDR5)-MYC inhibitors
using fragment-based methods and structure-based design
Selena Chacon Simon, Feng Wang, Lance R. Thomas, Jason Phan, Bin Zhao, Edward T
Olejniczak, Jonathan D Macdonald, J. Grace Shaw, Caden Schlund, William G. Payne, Joy
Creighton, Shaun Stauffer, Alex G. Waterson, William P Tansey, and Stephen W. Fesik
J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.0c00224 • Publication Date (Web): 30 Mar 2020
Downloaded from pubs.acs.org on March 30, 2020
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Journal of Medicinal Chemistry
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Page 9 of 63
Journal of Medicinal Chemistry
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Journal of Medicinal Chemistry
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Page 11 of 63
Journal of Medicinal Chemistry
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Journal of Medicinal Chemistry
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Journal of Medicinal Chemistry
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Journal of Medicinal Chemistry
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Page 15 of 63
Journal of Medicinal Chemistry
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Journal of Medicinal Chemistry
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Page 19 of 63
Journal of Medicinal Chemistry
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Journal of Medicinal Chemistry
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Journal of Medicinal Chemistry
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Journal of Medicinal Chemistry
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Journal of Medicinal Chemistry
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Journal of Medicinal Chemistry
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Journal of Medicinal Chemistry
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Journal of Medicinal Chemistry
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Journal of Medicinal Chemistry
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Page 29 of 63
Journal of Medicinal Chemistry
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ACS Paragon Plus Environment