Wang Michael S, Sussman Jonathan, Xu Jessica A, Patel Reema, Elghawy Omar, Rawla Prashanth
Hospital of the University of Pennsylvania, HUP 3400 Spruce St., Philadelphia, PA 19104, USA.
University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
Life (Basel). 2024 Dec 11;14(12):1645. doi: 10.3390/life14121645.
Polycomb repressive complex 2 (PRC2) is known to regulate gene expression and chromatin structure as it methylates H3K27, resulting in gene silencing. Studies have shown that PRC2 has dual functions in oncogenesis that allow it to function as both an oncogene and a tumor suppressor. Because of this, nuanced strategies are necessary to promote or inhibit PRC2 activity therapeutically. Given the therapeutic vulnerabilities and associated risks in oncological applications, a structured literature review on PRC2 was conducted to showcase similar cofactor competitor inhibitors of PRC2. Key inhibitors such as Tazemetostat, GSK126, Valemetostat, and UNC1999 have shown promise for clinical use within various studies. Tazemetostat and GSK126 are both highly selective for wild-type and lymphoma-associated EZH2 mutants. Valemetostat and UNC1999 have shown promise as orally bioavailable and SAM-competitive inhibitors of both EZH1 and EZH2, giving them greater efficacy against potential drug resistance. The development of other PRC2 inhibitors, particularly inhibitors targeting the EED or SUZ12 subunit, is also being explored with the development of drugs like EED 226. This review aims to bridge gaps in the current literature and provide a unified perspective on promising PRC2 inhibitors as therapeutic agents in the treatment of lymphomas and solid tumors.
已知多梳抑制复合物2（PRC2）可通过甲基化H3K27来调节基因表达和染色质结构，从而导致基因沉默。研究表明，PRC2在肿瘤发生中具有双重功能，使其既能作为癌基因发挥作用，又能作为肿瘤抑制因子发挥作用。因此，需要采取细致入微的策略来在治疗上促进或抑制PRC2的活性。鉴于肿瘤学应用中的治疗易损性和相关风险，我们对PRC2进行了结构化文献综述，以展示PRC2类似的辅因子竞争性抑制剂。诸如他泽司他、GSK126、瓦列司他和UNC1999等关键抑制剂在各项研究中已显示出临床应用前景。他泽司他和GSK126对野生型和淋巴瘤相关的EZH2突变体均具有高度选择性。瓦列司他和UNC1999已显示出作为EZH1和EZH2的口服生物利用性和SAM竞争性抑制剂的前景，使其对潜在耐药性具有更高的疗效。随着EED 226等药物的研发，其他PRC2抑制剂的开发，特别是针对EED或SUZ12亚基的抑制剂也在探索之中。本综述旨在弥合当前文献中的差距，并就有前景的PRC2抑制剂作为治疗淋巴瘤和实体瘤的治疗药物提供统一观点。
