Structure-Based Design of the Indole-Substituted Triazolopyrimidines as New EED–H3K27me3 Inhibitors for the Treatment of Lymphoma

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.

中断胚胎外胚层发育蛋白（embryonic ectoderm development, EED）与组蛋白H3K27me3的相互作用，是变构抑制多梳抑制复合体2（polycomb repressive complex 2, PRC2）用于癌症治疗的极具前景的策略。本研究报道了基于结构设计的新型三唑并嘧啶类EED抑制剂，该类抑制剂的结构特征为在C8位引入富电子吲哚环。尤为关键的是，化合物ZJH-16可直接结合EED（均相时间分辨荧光法（Homogeneous Time-Resolved Fluorescence, HTRF）半数抑制浓度IC50=2.72 nM，生物层干涉术（Bio-Layer Interferometry, BLI）解离常数KD=4.4 nM），并能强效抑制KARPAS422与Pfeiffer细胞的增殖。在上述两种细胞系中，ZJH-16均能选择性结合EED，并降低组蛋白H3K27三甲基化水平。ZJH-16可在KARPAS422细胞中抑制PRC2的基因沉默功能。ZJH-16具备良好的药代动力学（pharmacokinetics, PK）特性，其口服生物利用度优异（F=94.7%）。更为重要的是，经口给药后，ZJH-16在KARPAS422细胞异种移植模型中展现出显著的肿瘤消退效果，肿瘤生长抑制率近乎达到100%。ZJH-16优异的抗肿瘤药效与良好的药代动力学特性，支持其开展进一步的高级临床前研究，以推进淋巴瘤治疗的相关开发工作。