The histone lysine methyltransferase EZH2 has been implicated as a key component in cancer aggressiveness, metastasis and poor prognosis. This study discovered a new class of hexahydroisoquinolin derivatives as EZH2 inhibitors. A structure–activity relationship study showed that the steric hindrance was important to the activity for EZH2. A preliminary optimization study led to the discovery of several potent compounds with low nanomolar to sub-nanomolar potency for EZH2. Biological evaluation indicated that SKLB1049 was a highly potent with improved solubility compared to EPZ6438, SAM-competitive, and cell-active EZH2 inhibitor that decreased global H3K27me3 in SU-DHL-6 and Pfeiffer lymphoma cells in a concentration- and time-dependent manner. Further study indicated that SKLB1049 caused cell arrest in G₀/G₁ phase. These compounds would be useful as chemical tools to further explore the biology of EZH2 and provided us with a start point to develop new EZH2 inhibitors.

中文翻译：

---

新型1-甲基-3-氧代-2,3,5,6,7,8-六氢异喹啉类化合物作为潜在的EZH2抑制剂的设计，合成和生物学评估

组蛋白赖氨酸甲基转移酶EZH2被认为是癌症侵袭，转移和预后不良的关键因素。这项研究发现了一类新的六氢异喹啉衍生物作为EZH2抑制剂。结构-活性关系研究表明，空间位阻对EZH2的活性很重要。初步的优化研究导致发现几种对EZH2具有低纳摩尔至亚纳摩尔效价的有效化合物。生物学评估表明，与EPZ6438，具有SAM竞争性和细胞活性的EZH2抑制剂相比，SKLB1049具有更高的溶解度，可在SU-DHL-6和Pfeiffer淋巴瘤细胞中以浓度和时间依赖性方式降低整体H3K27me3。进一步的研究表明，SKLB1049导致G ₀细胞停滞。/ G ₁相。这些化合物可用作进一步探索EZH2生物学的化学工具，并为我们开发新的EZH2抑制剂提供了起点。