Project description:Biochemical interactions between WD40 repeat domain protein 5 (WDR5) and its various cellular partners such as Mixed Lineage Leukemia (MLL) and c-MYC are essential for sustaining oncogenesis in a range of human cancers. Thus, small molecules targeting WDR5 represent an attractive strategy for anti-cancer interventions. However, currently available inhibitors designed to interfere with WDR5 binding to a specific partner (such as OICR-9429 that blocks WDR5-MLL interaction) show a promising but rather partial therapeutic effect, presumably due to incomplete blockade of WDR5 functionality and interactions with various partners. Here, we report the first-in-class, OICR-9429-based proteolysis targeting chimeras (PROTACs) of WDR5, including a prototypic compound MS33 and a further optimized MS67, that achieve specific and efficient depletion of WDR5 in cancer cells. Such an effect is not seen with OICR-9429 or MS33/67 analogs that are incapable of E3 ligand conjugation. Medicinal chemistry, structural and cellular characterizations demonstrate that MS33 and MS67 bind both WDR5 and an E3 ligand VHL tightly, with MS67 showing a unique cooperative binding, an event that subsequently induces degradation of WDR5 through a VHL- and proteasome-dependent mechanism. Global proteomics profiling shows a highly specific effect of MS67 on WDR5. Genomics analysis further demonstrates that, relative to non-degrading inhibitors, MS67 is far more potent in suppressing overall transcription of WDR5-regulated genes crucially involved in oncogenesis and in reducing global H3K4 methylation, an enzymatic product of MLL/WDR5 complex. Importantly, using a panel of human MLL-rearranged acute myeloid leukemia (MLL-r AML) and pancreatic ductal adenocarcinoma (PDAC) cells, we found that, relative to non-degrading inhibitor controls, MS67 displays a superior anti-growth effect. MS67 also demonstrates optimal PK/PD properties in vivo and treatment with MS67 significantly suppressed tumorigenesis of MLL-r AML in tumor xenografted animal models. Together, this study reports the first-in-class PROTACs of WDR5 and demonstrates its advantageous efficacies in the treatment of WDR5-dependent cancers.

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ChIP-Seq H3K4me3 in Jurkat treated with either OICR-9429, PBIT or DMSO

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