Pyridone-based EZH2 inhibitor anticancer candidates: synthetic approaches, comparative analysis, and future perspectives

Enhancer of Zeste Homolog 2 (EZH2) is a major epigenetic regulator whose dysregulation drives oncogenesis through aberrant trimethylation of H3K27 and silencing tumor-suppressor genes. Pyridone-based small molecules have emerged as the dominant chemotype for targeting the SET domain of EZH2, enabling potent, selective, and mutation-tolerant inhibition across lymphoma and solid tumor models. This review introduces a comprehensive survey on the synthetic methodologies, scaffold design strategies, and structure-activity relationships underlying this pivotal class of EZH2 inhibitors. Emphasis is placed on advances in conformational restriction, tail-group optimization, and hybrid molecules linking EZH2 pharmacophores with PARP, BRD4, G9a, HSP90, and CDK9 modulators. Comparative ADME and drug-likeness analyses highlight key molecular determinants of potency and pharmacokinetic performance. Finally, an outline is given on emerging opportunities and challenges shaping the future of pyridone-based EZH2 inhibitor rational design and optimization strategies for the development of next-generation anticancer candidates.