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

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Structure-Based Design of the Indole-Substituted Triazolopyrimidines as New EED–H3K27me3 Inhibitors for the Treatment of Lymphoma
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-12-29 , DOI: 10.1021/acs.jmedchem.2c02028
Guanjun Dong ₁ , Jiahui Zuo ₁ , Junlin Yu ₂ , Jiale Xu ₁ , Ge Gao ₁ , Guo-Bo Li ₂ , Wen Zhao ₁ , Bin Yu ₁

Affiliation

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 K_D = 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.

中文翻译：

基于结构的吲哚取代三唑并嘧啶设计作为用于治疗淋巴瘤的新型 EED–H3K27me3 抑制剂

中断胚胎外胚层发育 (EED)–H3K27me3 相互作用是变构抑制多梳抑制复合物 2 (PRC2) 用于癌症治疗的一种很有前途的策略。在这项工作中，我们报告了新的基于三唑并嘧啶的 EED 抑制剂的基于结构的设计，其结构特征是 C8 位置的富电子吲哚环。特别是，ZJH-16 直接结合 EED（HTRF IC ₅₀ = 2.72 nM，BLI K _D = 4.4 nM）并有效抑制 KARPAS422 和 Pfeiffer 细胞的生长。在这两个细胞中，ZJH-16 选择性地与 EED 结合并降低 H3K27 三甲基化水平。ZJH-16 抑制 KARPAS422 细胞中 PRC2 的基因沉默功能。ZJH-16 具有良好的药代动力学 (PK) 特性和出色的口服生物利用度 (F = 94.7%)。更重要的是，ZJH-16在口服给药后在KARPAS422异种移植模型中显示出强劲的肿瘤消退，肿瘤生长抑制达到近100%。ZJH-16 强大的抗肿瘤功效和良好的 PK 特征保证了淋巴瘤治疗的进一步高级临床前开发。

更新日期：2022-12-29

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