Rinzimetostat——一种用于治疗前列腺癌、具有同类最佳特性的变构EED抑制剂，在临床前研究中于PRC2甲基转移酶耐药情形下有效

Polycomb repressive complex 2 (PRC2) regulates transcription by trimethylating histone H3 at lysine 27 (H3K27me3) to impact cell growth and differentiation. PRC2 dysregulation is a poor prognostic in prostate cancer and promotes lineage plasticity and therapeutic resistance. The key PRC2 subunits, EED, SUZ12, and EZH1 or EZH2, are required for chromatin recruitment and histone methyltransferase activity. In vivo prostate cancer studies have shown PRC2 inhibitor combinations with AR inhibitors prolong survival and inhibit tumor growth. Rinzimetostat (ORIC-944) is a next-generation allosteric PRC2 inhibitor targeting EED, with best-in-class drug properties in preclinical studies including solubility, ADME/PK, and excellent half-life. In assessing rinzimetostat as a potential best-in-class PRC2 inhibitor, further preclinical studies investigated targeting EED vs EZH2 or EZH1/2 in the context of potential acquired resistance mechanisms. EZH1 paralog compensation has the potential to be a tumor escape mechanism for EZH2 inhibitors, therefore inhibitors of EED, EZH2, and EZH1/2 were assessed in biochemical assays on PRC2 complexes that contained either EZH1 or EZH2 as the enzymatic subunit. Rinzimetostat had comparable potency on PRC2 with either EZH1 or EZH2 in the complex, while other PRC2 inhibitors had reduced activity on EZH1-containing complexes. In prostate cancer cells engineered to overexpress EZH1, the EZH2 inhibitors tazemetostat and mevrometostat lost potency whereas rinzimetostat, an EED inhibitor, retained activity. We next investigated the activity of PRC2 inhibitors in the context of an EZH2 inhibitor acquired resistance mutation observed in the clinic. As predicted from drug binding sites, EZH2 Y666N mutant-expressing prostate cancer cells were impervious to H3K27me3 reduction by EZH2 inhibitors mevrometostat or tazemetostat; however, rinzimetostat inhibited H3K27me3 in EZH2 Y666N mutant cells. Cells engineered with an EZH1/2 inhibitor acquired resistance mutant, EED H213R, demonstrated loss of effectiveness upon treatment with EZH1/2 inhibitor valemetostat, whereas rinzimetostat equally inhibited H3K27me3 in the EED mutant and wildtype settings. Together, these data suggest that rinzimetostat, as an EED inhibitor, has the potential for superiority in EZH2 and EZH1/2 inhibitor-acquired resistance contexts. In summary, preclinical results demonstrate potential best-in-class drug properties of rinzimetostat, as well as the potential superiority of targeting EED to address paralog compensation and avoid acquired resistance mechanisms that may be liabilities for EZH2 or EZH1/2 inhibitors. Rinzimetostat is under clinical evaluation in combination with AR inhibitors in a global Phase 1b study (NCT05413421).