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

被引:12
作者
Dong, Guanjun [1 ,2 ]
Zuo, Jiahui [1 ,2 ]
Yu, Junlin [3 ]
Xu, Jiale [1 ,2 ]
Gao, Ge [1 ,2 ]
Li, Guo-Bo [3 ]
Zhao, Wen [1 ,2 ]
Yu, Bin [1 ,2 ]
机构
[1] Zhengzhou Univ, State Key Lab Esophageal Canc Prevent & Treatment, Zhengzhou 450001, Peoples R China
[2] Zhengzhou Univ, Sch Pharmaceut Sci, Zhengzhou 450001, Peoples R China
[3] Sichuan Univ, West China Sch Pharm, Dept Med Chem, Key Lab Drug Targeting & Drug Delivery Syst Minit, Chengdu 610041, Peoples R China
关键词
REPRESSIVE COMPLEX 2; PRC2; INHIBITOR; PROTEIN EED; EZH2; DISCOVERY; CHROMATIN; POTENT; SUZ12; METHYLATION; IDENTITY;
D O I
10.1021/acs.jmedchem.2c02028
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
引用
收藏
页码:1063 / 1081
页数:19
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