Small molecule inhibitors of the WDR5-MYC interaction

Abstract

Multiple cellular processes, including cell growth, the cell cycle, metabolism, differentiation, transformation, and apoptosis are regulated by MYC proteins. 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. Nonetheless, targeting MYC itself has been challenging as it is an intrinsically disordered protein. Recently, we discovered that WDR5 binds to MYC and is a critical cofactor required for the recruitment of MYC to its target genes. Therefore, we propose that by discovering small molecules capable of disrupting this protein-protein interaction, we will be able to determine the viability of this approach as a novel treatment option for MYC-dependent cancers. Utilizing a high-throughput screening campaign and subsequent structure-guided design, we identified small molecule inhibitors of this interaction with potent in vitro binding affinity. These compounds display poor physicochemical properties and are not suitable for in vivo studies. In order to identify additional chemical matter, we conducted an NMR-based fragment screen and, using a structure-based approach, we merged a fragment hit with the previously identified series. Compounds in this new series can disrupt the WDR5-MYC interaction in cells and as a consequence, we observed a reduction of MYC localization to chromatin. Overall, this work suggests that small molecules can bind WDR5 at the WBM site and the compounds discovered here can be used to further interrogate the effects of disrupting the WDR5-MYC interaction. The druggability of this site remains uncertain; however, further optimization of the compounds may aid identify a possible therapeutic window.