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.