Pharmacological Advancements of PRC2 in Cancer Therapy: A Narrative Review

Area of Science:

• Epigenetics
• Molecular Biology
• Oncology

Background:

• Polycomb repressive complex 2 (PRC2) epigenetically regulates gene expression via H3K27 methylation, impacting chromatin structure and gene silencing.
• PRC2 exhibits dual roles in oncogenesis, acting as both an oncogene and a tumor suppressor, necessitating nuanced therapeutic strategies.
• Targeting PRC2 offers therapeutic vulnerabilities and risks in oncological applications, driving research into specific inhibitor development.

Purpose of the Study:

• To conduct a structured literature review on Polycomb repressive complex 2 (PRC2) inhibitors.
• To identify and showcase cofactor competitor inhibitors of PRC2 with therapeutic potential.
• To provide a unified perspective on promising PRC2 inhibitors for treating lymphomas and solid tumors.

Main Methods:

• Structured literature review of scientific studies on PRC2 and its inhibitors.
• Analysis of key PRC2 inhibitors, including Tazemetostat, GSK126, Valemetostat, and UNC1999.
• Exploration of emerging PRC2 inhibitors targeting EED or SUZ12 subunits, such as EED 226.

Main Results:

• Tazemetostat and GSK126 demonstrate high selectivity for wild-type and lymphoma-associated EZH2 mutants.
• Valemetostat and UNC1999 are orally bioavailable, SAM-competitive inhibitors of EZH1/EZH2, offering potential against drug resistance.
• Development of novel PRC2 inhibitors targeting EED or SUZ12 subunits is ongoing, expanding therapeutic options.

Conclusions:

• PRC2 inhibitors represent a promising therapeutic avenue for lymphomas and solid tumors.
• Selective inhibition of PRC2 components offers targeted cancer treatment strategies.
• Continued research into diverse PRC2 inhibitors is essential for overcoming therapeutic challenges and drug resistance.