Therapeutic horizons in the development of PROTAC-based EZH2 inhibitors: recent achievements, comparative analysis, and future perspectives.

ABSTRACT: EZH2, a histone methyltransferase and the catalytic subunit of the polycomb repressive complex 2 (PRC2), plays a pivotal role in tumor epigenetics through transcriptional repression of tumor suppressor genes. Despite the clinical success of tazemetostat, classical small-molecule inhibitors face limitations related to incomplete target occupancy, adaptive resistance, and non-catalytic EZH2 functions. These challenges have driven a paradigm shift toward proteolysis-targeting chimeras (PROTACs)-bifunctional molecules that inhibit EZH2 through E3 ligase-mediated ubiquitination and proteasomal degradation. This review discusses the design principles, synthetic approaches, structural diversity, and pharmacological profiles of recently developed VHL-, CRBN-, and cIAP-recruiting EZH2 inhibitors re

SUBMITTER: S Abulkhair H 

PROVIDER: S-EPMC12800930 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature