GSE203101
Structure-Based Discovery of Potent WD Repeat Domain 5 Inhibitors that Demonstrate Efficacy and Safety in Preclinical Animal Models
WD repeat domain 5 (WDR5) is a core scaffolding component of many multi-protein complexes that perform a variety of critical chromatin-centric processes in the nucleus. WDR5 is component of the mixed lineage leukemia MLL/SET complex and localizes MYC to chromatin tumor-critical target genes. Overexpression of WDR5 promotes oncogenesis in a variety of human cancers that are often associated with poor prognoses. Thus, WDR5 has been recognized as an attractive therapeutic target for treating both solid and hematological tumors. Previously, small-molecule WDR5 WIN-site inhibitors and WDR5 degraders have demonstrated robust in vitro cellular efficacy in cancer cell lines and established the therapeutic potential of WDR5. However, these agents have not demonstrated significant in vivo efficacy at pharmacologically relevant doses by oral administration in animal disease models. We have discovered WDR5 WIN-site inhibitors that feature bicyclic heteroaryl P7 units through structure-based design and address the limitations of our previous series of small-molecule inhibitors. Importantly, our new lead compounds exhibit enhanced on-target potency, excellent oral pharmacokinetic (PK) profiles, and potent dose-dependent in vivo efficacy in a mouse MV4:11 subcutaneous xenograft model by oral dosing. Furthermore, these in vivo probes show excellent tolerability under a repeated high dose regimen in rodents to demonstrate the safety of the WDR5 WIN site inhibition mechanism. Collectively, our results provide strong support for WDR5 WIN-site inhibitors to be utilized as potential anticancer therapeutics. Overall design: MV4:11 cells were treated with DMSO or WIN site inhibitors C16 and C10. RNA-Seq was used to monitor long-term transcriptional changes.