Targeting EED as a key PRC2 complex mediator toward novel epigenetic therapeutics

Qichao Bao; Anil Kumar; Daqing Wu; Jia Zhou

doi:10.1016/j.drudis.2024.103986

Targeting EED as a key PRC2 complex mediator toward novel epigenetic therapeutics

Drug Discov Today. 2024 Apr 18;29(6):103986. doi: 10.1016/j.drudis.2024.103986. Online ahead of print.

Authors

Qichao Bao¹, Anil Kumar¹, Daqing Wu², Jia Zhou³

Affiliations

¹ Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
² Center for Cancer Research and Therapeutic Development and Department of Biological Sciences, Clark Atlanta University, Atlanta, GA 30314, USA.
³ Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA. Electronic address: jizhou@utmb.edu.

PMID: 38642703
DOI: 10.1016/j.drudis.2024.103986

Abstract

EED within the PRC2 complex is crucial for chromatin regulation particularly in tumor development, making its inhibition a promising epigenetic therapeutic strategy. Significant advancement in PRC2 inhibitor development has been achieved with an approved EZH2 inhibitor in the market and with others in the clinical trials. However, current EZH2 inhibitors are limited to specific blood cancers and encounter therapeutic resistance. EED stabilizes PRC2 complex and enhances its activity through unique allosteric mechanisms, thereby acting as both a scaffold protein and a recognizer of H3K27me3 making it an attractive drug target. This review provides an overview of epigenetic therapeutic strategies targeting EED, including allosteric inhibitors, PPI inhibitors, and PROTACs, together with brief discussions on the relevant challenges, opportunities, and future directions.

Keywords: EED; PRC2; PROTACs; cancer therapy; epigenetic therapeutics; protein–protein interaction modulators.

Publication types

Review