EZH1/2

Class

small molecule

Notes

original target text: EZH1/2 inhibitor

EZH1 and EZH2 are catalytic subunits of Polycomb Repressive Complex 2 (PRC2), an enzyme complex that adds methyl groups to a specific site on histone proteins (histone H3, lysine 27), a modification known as H3K27 trimethylation. This mark compacts chromatin and silences the genes it covers, including tumor suppressor genes that normally restrain cell growth. In several cancers, mutations or overexpression involving EZH2 lead to excessive H3K27 methylation and inappropriate silencing of these growth-restraining genes, allowing malignant cells to proliferate unchecked. Small-molecule inhibitors that block the catalytic activity of EZH1/2 aim to reverse this silencing, reactivating tumor suppressor and differentiation programs. Targeting both EZH1 and EZH2, rather than EZH2 alone, is a deliberate design choice: EZH1 can partially substitute for EZH2 within PRC2, particularly in cells that are not rapidly dividing, so inhibiting EZH2 alone may leave residual methyltransferase activity intact. Dual inhibition is intended to produce more complete and durable suppression of H3K27 methylation across a broader range of tumor cell states. This mechanism is under investigation primarily in hematologic malignancies such as lymphomas, where EZH2 mutations are recurrent, and in certain solid tumors where PRC2 activity contributes to a dedifferentiated, growth-promoting cellular state.