Discovery of a First-In-Class MPP8 Antagonist to Reverse Lineage Plasticity in Treatment-Resistant Prostate Cancer

The overarching goal of this proposal is to better understand the role of MPP8 in lineage plasticity and EMT in mCRPC and NEPC, discover a potent first-in-class antagonist of MPP8, and evaluate MPP8 chemical antagonism as a therapeutic strategy for EMT reversal. During this reporting period, we showed that MPP8 knockdown by siRNAs inhibits proliferation and cell motility, and cell invasion. We also showed that MPP8 knockdown reduces SIRT1 and vimentin protein (but does not increase E-cadherin). Using UNC7713 and second-generation compound UNC8850, we completed labeling studies and showed UNC8850 has 3.5-fold increased labeling compared to UNC7713. We performed whole-genome proteomic analysis of cells treated with UNC7713 and confirmed MPP8 is a target of UNC7713 while identifying 15 additional novel targets related to MPP8 antagonism. We confirmed that UNC7713 potently inhibits cell proliferation and clonogenic potential, inhibits cell migration and invasion, and causes apoptosis. We also discovered that UNC7713 is lethal to mice upon repeat dosing, but when formulated within liposomes is not immediately lethal to mice.