Polycomb repressive complex 2 (PRC2) has been shown to play a major role in transcriptional silencing in part by installing methylation marks on lysine 27 of histone 3. Dysregulation of PRC2 function correlates with certain malignancies and poor prognosis. EZH2 is the catalytic engine of the PRC2 complex and thus represents a key candidate oncology target for pharmacological intervention. Here we report the optimization of our indole-based EZH2 inhibitor series that led to the identification of CPI-1205, a highly potent (biochemical IC₅₀ = 0.002 μM, cellular EC₅₀ = 0.032 μM) and selective inhibitor of EZH2. This compound demonstrates robust antitumor effects in a Karpas-422 xenograft model when dosed at 160 mg/kg BID and is currently in Phase I clinical trials. Additionally, we disclose the co-crystal structure of our inhibitor series bound to the human PRC2 complex.

中文翻译：

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（R）-N -（（4-甲氧基-6-甲基-2-氧代-1,2，二氢吡啶基-3-基）甲基）-2-甲基-1-（1-（1-（2， 2,2-三氟乙基）哌啶丁-4-基）乙基）-1 H-吲哚-3-羧酰胺（CPI-1205）是组蛋白甲基转移酶EZH2的强效和选择性抑制剂，适用于B细胞淋巴瘤的I期临床试验

已显示，通过在组蛋白3的赖氨酸27上安装甲基化标记，多梳抑制复合物2（PRC2）在转录沉默中起主要作用。PRC2功能失调与某些恶性肿瘤和不良预后相关。EZH2是PRC2复合物的催化引擎，因此代表了药理学干预的主要候选肿瘤学靶标。在这里，我们报告了我们基于吲哚的EZH2抑制剂系列的优化，该系列导致了CPI-1205的鉴定，CPI-1205是高效的（生化IC ₅₀ = 0.002μM，细胞EC ₅₀= 0.032μM）和EZH2的选择性抑制剂。当以160 mg / kg BID剂量给药时，该化合物在Karpas-422异种移植模型中显示出强大的抗肿瘤作用，目前处于I期临床试验中。另外，我们公开了与人PRC2复合物结合的抑制剂系列的共晶体结构。