Discovery of a First-in-Class MPP8 Antagonist to Reverse Lineage Plasticity in Bladder Cancer
Abstract
Bladder cancer (BC) is a common and deadly disease, and despite recent treatment advances, metastatic BC (mBC) remains incurable. Mutations in genes that encode epigenetic/chromatin modifier proteins are common in mBC, with >90 percent of tumors harboring at least one inactivating mutation. The epigenetic reader protein MPP8 recognizes the histone-3-lysine-9-trimethyl (H3K9me3) region of target gene promoters, and recruits transcription factors associated with cell proliferation and metastasis. UNC7713 was developed as a covalent antagonist to disrupt MPP8 binding to H3K9me3. Here, we explored whether UNC7713 potently inhibits cell proliferation, migration, and viability in preclinical models of BC. During this reporting period, we demonstrated knockdown of MPP8 using siRNA (siMPP8) significantly limits cell proliferation, migration/invasion and viability in 5637, TCCSUP and UM-UC-3 bladder cancer cell lines. In addition, we were not able to show that siMPP8 impacts expression of SIRT1 and Zeb1, but we did demonstrate that MPP8 co-immunoprecipitated with TASOR, Zeb1, Zeb2, Snail, and Slug. This suggests interactions between MPP8 and these transcription factors can lead to repression of tumor suppressor genes. While we continue to struggle to link MPP8 knockdown or chemical antagonism with EMT, we did demonstrate that siMPP8 activates IL6 and IFNB1. Last, during this period we were able to confirm data from the previous reporting period and showed that UNC7713 has submicromolar potency to inhibit proliferation, migration and viability in TCCSUP and UMUC-3 cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2023
- Accession Number
- AD1226992
Entities
People
- Daniel J. Crona
Organizations
- University of North Carolina at Chapel Hill