Chacón Simon, Selena, Wang, Feng, Thomas, Lance R, Phan, Jason, Zhao, Bin, Olejniczak, Edward T, Macdonald, Jonathan D, Shaw, J Grace, Schlund, Caden, Payne, William, Creighton, Joy, Stauffer, Shaun R, Waterson, Alex G, 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