EEDi-5273 (APG-5918): A Comprehensive Profile of a Potential Best-in-Class EED Inhibitor for Oncologic and Hematologic Disorders

The Evolving Landscape of PRC2 Inhibition: From EZH2 to EED

The Central Role of the PRC2 Complex in Epigenetic Gene Silencing and Cancer

The Polycomb Repressive Complex 2 (PRC2) is a fundamental epigenetic regulator essential for controlling gene expression during embryonic development and maintaining cellular identity in adult tissues.[1] Its primary biological function is to catalyze the mono-, di-, and trimethylation of histone H3 at lysine 27 (H3K27), with trimethylation (H3K27me3) being a potent repressive mark associated with chromatin compaction and transcriptional silencing.[1] The core of the human PRC2 complex consists of four key protein subunits that must assemble to achieve catalytic activity: a catalytic subunit, either Enhancer of Zeste Homolog 2 (EZH2) or its homolog EZH1; and two essential non-catalytic scaffolding components, Embryonic Ectoderm Development (EED) and Suppressor of Zeste 12 (SUZ12).[1]

In the context of oncology, the dysregulation of PRC2 function is a well-established driver of tumorigenesis across a spectrum of human cancers.[1] Overexpression, amplification, or the acquisition of gain-of-function mutations in PRC2 components, particularly EZH2, is frequently observed in both hematologic malignancies and solid tumors, including various lymphomas, prostate cancer, and breast cancer.[8] This aberrant activity leads to the pathological silencing of critical tumor suppressor genes, thereby promoting uncontrolled cell proliferation, blocking differentiation, and contributing to malignant transformation.[8] Consequently, elevated levels of EZH2 or other PRC2 components are often correlated with advanced tumor grade and poor patient prognosis, firmly establishing the PRC2 complex as a high-value therapeutic target in oncology.[8]