Discovery of First-in-class WDR5 PROTACs as a Novel Therapeutic Strategy for MLL-rearranged Leukemias

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PROJECT SUMMARY The main objective of the parent project is to develop WDR5 small-molecule degraders as anticancer therapeutics. WD40 repeat domain protein 5 (WDR5), which functions an essential subunit of the MLL histone methyltransferase complex, is critical for gene transcription regulations and essential for sustaining oncogenesis in human cancers. WDR5 is also implicated in Alzheimer’s Disease (AD), and WDR5 inhibitors are efficacious in improving prefrontal cortex synaptic function and memory-related behaviors in AD mice. The parent project does not focus on AD. This administrative supplement is in response to the Notice of Special Interest NOT-AG- 22-025, Alzheimer’s-Focused Administrative Supplements for NIH Grants that are Not Focused on Alzheimer’s Disease. Some cancer patients also suffer from AD, a devastating neurodegenerative disorder, which currently has no effective disease-modifying therapeutics. Synaptojanin 1 (synj1), the main phosphoinositol bisphosphate degrading enzyme in the brain and synapses, plays a critical role in AD pathology. Increased synj1 expression and activities have been associated with cognitive decline and pathological processes of AD. Synj1 is also implicated in cancer. It is overexpressed in various cancers, and high expression of synj1 correlates with poor prognosis in cancer patients. In our preliminary studies, compounds that lower the synj1 protein level have been discovered. The lead synj1-lowering compounds were efficacious in several AD mouse models. In this administrative supplement, we propose to conduct a lead optimization campaign to generate optimized synj1- lowering compounds with improved potency, selectivity and brain penetration. The synj1-lowering compounds generated in this administrative supplement could ultimately be developed into effective therapeutics for the treatment of AD, which will also benefit cancer patients who suffer from AD. These synj1-lowering compounds could also be useful anticancer therapeutics.