Enhancer of Zeste Homolog 2 (EZH2) is a histone methyltransferase that catalyzes the methylation of histone H3 lysine 27, a modification frequently dysregulated in various cancers. EZH2 plays critical roles in cell proliferation, differentiation, and gene silencing, and its abnormal overexpression is closely associated with tumor aggressiveness and poor prognosis. Inhibiting EZH2 can reactivate tumor suppressor genes and thereby suppress cancer cell growth and metastasis. Although several EZH2 inhibitors, including small molecules and nucleic acid drugs, have been developed and some have entered clinical trials, their specificity and potency still require further optimization. Tazemetostat is the first FDA-approved EZH2 inhibitor for relapsed or refractory follicular lymphoma, while other agents such as EPZ-6438 and GSK126 show promising preclinical antitumor activity. This review summarizes the association between EZH2 and tumors, and the mechanisms and pharmacological properties of EZH2 inhibitors. Future research directions and challenges are also discussed to facilitate the development of EZH2-targeted anticancer therapies strategies.
Yihang Wang, Chaojiang Fu, Jinrui Ping et al.· Current Medicinal Chemistry· 0 citations
The epigenetic regulator protein arginine methyltransferase 5 (PRMT5) is aberrantly overexpressed in triple-negative breast cancer (TNBC) and represents a promising therapeutic target. Currently reported PRMT5-targeting PROTAC degraders (MS4322 and MS115) are both derived from a tetrahydroisoquinoline scaffold. These compounds require treatment for more than five days to exert effective antiproliferative activities, and no in vivo antitumor efficacy has been reported. To address these limitations, we adopted the carbazole-based PRMT5 inhibitor PJ-68, which features a lower molecular weight and a more accessible linker attachment site. Herein, we reported a series of novel PRMT5 degraders with carbazole scaffold. The representative compound YZ-17 degraded PRMT5 (DC50 = 2.2 μM in HCC1806 and 3.3 μM in HCC1937 cells) and its adaptor protein MEP50 (DC50 = 2.0 μM and 2.9 μM, respectively) within 24 h. YZ-17 also suppressed PRMT5-mediated symmetric dimethylarginine (sDMA) modification and colony formation, induced G1 phase cell cycle arrest, and displayed favorable antiproliferative activities across several TNBC cell lines (IC50 = 2.6 - 3.7 μM). Importantly, YZ-17 showed in vivo efficacy in an HCC1806 xenograft model, achieving a tumor growth inhibition (TGI) of 44.12% at 30 mg/kg (i.p., every other day) without obvious toxicity. Collectively, YZ-17 represents a structurally novel PRMT5 degrader with rapid onset of action, effective in vitro and in vivo anti-TNBC activity, offering a distinct chemical tool for further functional studies of PRMT5.
Yuzhan Li, Yaxun Guo, Dazhao Mi et al.· European journal of medicina...· 0 citations