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- W4313277449 abstract "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." @default.
- W4313277449 created "2023-01-06" @default.
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- W4313277449 date "2022-12-29" @default.
- W4313277449 modified "2023-10-15" @default.
- W4313277449 title "Structure-Based Design of the Indole-Substituted Triazolopyrimidines as New EED–H3K27me3 Inhibitors for the Treatment of Lymphoma" @default.
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- W4313277449 doi "https://doi.org/10.1021/acs.jmedchem.2c02028" @default.
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