Abstract P089: Discovery of novel small-molecule inhibitors for an epigenetic modulator WDR5

Abstract

Abstract WDR5, the histone H3 lysine 4 (H3K4) presenter WD repeat-containing protein 5, is a widely expressed protein that forms complexes with H3K4 methyltransferases MLL1-MLL4 and partner proteins including RBBP5, ASH2L, DPY30, and MYC. It plays an important role in epigenetic machinery assembly, transcriptional regulation, and chromatin regulation. As a result, WDR5 has become an increasingly attractive target for therapeutic intervention against cancers, including mixed-lineage leukemia, neuroblastoma, breast cancer, bladder cancer, pancreatic cancer, and colorectal cancer. Using its proprietary chemoproteomic platform IMTACTM (Isobaric Mass Tagged Affinity Characterization), BridGene has screened its unique covalent library against live-cell proteomes and discovered small-molecule ligands for hundreds of hard-to-drug targets, including transcription factors, splicing factors, epigenetic modulators, and E3 ligases. WDR5 is among these targets that BridGene has discovered a novel ligand for. Preliminary characterization of the “hit” compound, BGS1989, showed that it interacts with WDR5 in a dose-dependent manner, and it can inhibit MLL1 methyltransferase activity at low µM potency. After one round of chemical optimization, we identified an improved inhibitor BGS2597 that has ~200 nM potency in the WDR5-MLL interaction and H3K4 methylation assays. Additional optimizations are being conducted to further improve BGS2597’s activity and selectivity for WDR5. Comprehensive characterizations are being performed to delineate which of WDR5’s functions are modulated by BGS2597. The WDR5 inhibitor discovered using IMTACTM platform provides an excellent starting point for the development of new drugs targeting WDR5-dependent cancers. Citation Format: Cindy Huang, Shirley Guo, Ping Cao. Discovery of novel small-molecule inhibitors for an epigenetic modulator WDR5 [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P089.