Small Molecule Approaches for Targeting the Polycomb Repressive Complex 2 (PRC2) in Cancer

J Med Chem. 2020 Dec 24;63(24):15344-15370. doi: 10.1021/acs.jmedchem.0c01344. Epub 2020 Dec 7.


The polycomb repressive complex 2 (PRC2) is composed of three core subunits, enhancer of zeste 2 (EZH2), embryonic ectoderm development (EED), and suppressor of zeste 12 (SUZ12), along with a number of accessory proteins. It is the key enzymatic protein complex that catalyzes histone H3 lysine 27 (H3K27) methylation to mediate epigenetic silencing of target genes. PRC2 thus plays essential roles in maintaining embryonic stem cell identity and in controlling cellular differentiation. Studies in the past decade have reported frequent overexpression or mutation of PRC2 in various cancers including prostate cancer and lymphoma. Aberrant PRC2 function has been extensively studied and proven to contribute to a large number of abnormal cellular processes, including those that lead to uncontrolled proliferation and tumorigenesis. Significant efforts have recently been made to develop small molecules targeting PRC2 function for potential use as anticancer therapeutics. In this review, we describe recent approaches to identify and develop small molecules that target PRC2. These various strategies include the inhibition of the function of individual PRC2 core proteins, the disruption of PRC2 complex formation, and the degradation of its subunits.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / therapeutic use
  • Enhancer of Zeste Homolog 2 Protein / antagonists & inhibitors
  • Enhancer of Zeste Homolog 2 Protein / metabolism
  • Histones / metabolism
  • Humans
  • Indoles / chemistry
  • Indoles / metabolism
  • Indoles / therapeutic use
  • Neoplasms / drug therapy
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Polycomb Repressive Complex 2 / chemistry
  • Polycomb Repressive Complex 2 / metabolism*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / metabolism
  • Small Molecule Libraries / therapeutic use
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • Histones
  • Indoles
  • Small Molecule Libraries
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2