Design, synthesis, and biological evaluation of novel pyridazinone-based EED inhibitors for prostate cancer

Abstract

Aberrant activity of histone methyltransferase polycomb repressive complex 2 (PRC2) is associated with cancers and other diseases. Recently, compounds that bind to the EED subunit of PRC2 have emerged as allosteric inhibitors of PRC2, suggesting that targeting EED represents a novel strategy for human diseases. In this study, we designed and synthesized a new array of pyridazinone-based EED inhibitors derived from hit 6 identified through virtual screening, which was further optimized via extensive structure−activity relationship (SAR) studies. Ultimately, molecule 39 (IC₅₀= 0.62 μM) was identified as a potent EED inhibitor, which not only exhibited potent anti-proliferative activity and high selectivity against prostate cancer PC3 cells, but also could significantly suppress its colony formation and migration. Importantly, compound 39 showed acceptable PK properties and robust tumor regression in the PC3 xenograft model with the tumor growth inhibition reaching nearly 80%. Overall, our study identifies pyridazinone derivative 39 as a novel EED inhibitor, emerging as a promising lead compound warrant further optimization and development for prostate cancer.