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

Chacón Simon, Selena and Wang, Feng and Thomas, Lance R and Phan, Jason and Zhao, Bin and Olejniczak, Edward T and Macdonald, Jonathan D and Shaw, J Grace and Schlund, Caden and Payne, William and Creighton, Joy and Stauffer, Shaun R and Waterson, Alex G and Tansey, William P and Fesik, Stephen W (2020) Discovery of WD Repeat-Containing Protein 5 (WDR5)-MYC Inhibitors Using Fragment-Based Methods and Structure-Based Design. Journal of medicinal chemistry, 63 (8). pp. 4315-4333. ISSN 1520-4804

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.

Item Type: Article
Date Deposited: 03 May 2020 00:45
Last Modified: 03 May 2020 00:45
URI: https://oak.novartis.com/id/eprint/42213

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