EEDi-5285: An Exceptionally Potent, Efficacious, and Orally Active Small-Molecule Inhibitor of Embryonic Ectoderm Development

Inhibition of embryonic
ectoderm development (EED) is a new cancer
therapeutic strategy. Herein, we report our discovery of EEDi-5285
as an exceptionally potent, efficacious, and orally active EED inhibitor.
EEDi-5285 binds to the EED protein with an IC50 value of
0.2 nM and inhibits cell growth with IC50 values of 20
pM and 0.5 nM in the Pfeiffer and KARPAS422 lymphoma cell lines, respectively,
carrying an EZH2 mutation. EEDi-5285 is approximately 100 times more
potent than EED226 in binding to EED and >300 times more potent
than
EED226 in inhibition of cell growth in the KARPAS422 cell line. EEDi-5285
has excellent pharmacokinetics and achieves complete and durable tumor
regression in the KARPAS422 xenograft model in mice with oral administration.
The cocrystal structure of EEDi-5285 in a complex with EED defines
the precise structural basis for their high binding affinity. EEDi-5285
is the most potent and efficacious EED inhibitor reported to date.