Structure-Based Design of the Indole-Substituted Triazolopyrimidines as New EED-H3K27me3 Inhibitors for the Treatment of Lymphoma
Structure-Based Design of the Indole-Substituted Triazolopyrimidines as New EED-H3K27me3 Inhibitors for the Treatment of Lymphoma
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基于结构的吲哚取代三唑并嘧啶类药物的设计，作为治疗淋巴瘤的新型 EED–H3K27me3 抑制剂
DOI：
10.1021/acs.jmedchem.2c02028
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发表时间：
2022-12-29
影响因子：
7.3
通讯作者：
Yu, Bin
中科院分区：
文献类型：
--
作者：
Dong, Guanjun;Zuo, Jiahui;Yu, Bin
中断胚胎外胚层发育（EED）-H3 K27 me 3相互作用代表了变构抑制多梳抑制复合物2（PRC 2）用于癌症治疗的有希望的策略。在这项工作中，我们报告了基于结构的设计新的三唑并嘧啶为基础的EED抑制剂，其结构特点是在C8位置的富电子吲哚环。特别地，ZJH-16直接结合EED（HTRF IC 50 = 2.72 nM，BLI KD = 4.4 nM）并有效抑制KARPAS 422和Pfeiffer细胞的生长。在这两种细胞中，ZJH-16选择性地与EED结合并降低H3 K27三甲基化水平。ZJH-16抑制KARPAS 422细胞PRC 2基因沉默功能。ZJH-16具有良好的药代动力学（PK）特征，具有良好的口服生物利用度（F = 94.7%）。更重要的是，ZJH-16在口服给药后在KARPAS 422异种移植模型中显示出稳健的肿瘤消退，肿瘤生长抑制达到接近100%。ZJH-16强大的抗肿瘤疗效和有利的PK特征保证了淋巴瘤治疗的进一步临床前开发。
Interrupting the embryonic ectoderm development (EED)- H3K27me3 interaction represents a promising strategy to allosterically inhibit polycomb repressive complex 2 (PRC2) for cancer therapy. In this work, we report the structure-based design of new triazolopyrimidine-based EED inhibitors, which structurally feature the electron-rich indole ring at the C8 position. Particularly, ZJH-16 directly binds to EED (HTRF IC50 = 2.72 nM, BLI KD = 4.4 nM) and potently inhibits the growth of KARPAS422 and Pfeiffer cells. In both cells, ZJH-16 is selectively engaged with EED and reduces H3K27 trimethylation levels. ZJH-16 inhibits the gene silencing function of PRC2 in KARPAS422 cells. ZJH-16 possesses favorable pharmacokinetic (PK) profiles with an excellent oral bioavailability (F = 94.7%). More importantly, ZJH-16 shows robust tumor regression in the KARPAS422 xenograft model after oral administration with the tumor growth inhibition reaching nearly 100%. The robust antitumor efficacy and favorable PK profiles of ZJH-16 warrant further advanced preclinical development for lymphoma treatment.