Inhibition of PRC2 activity via an allosteric mechanism offers a promising new therapeutic strategy for the treatment of PRC2-dependent cancers. We report herein the discovery of exceptionally potent and efficacious EED inhibitors. By conformational restriction of a previously reported EED inhibitor, we obtained a potent lead compound. Further optimization of the lead yielded a series of exceptionally potent and orally active EED inhibitors. The best compound UM-EEDi-5273 binds to EED with an IC50 value of 0.2 nM and inhibits the KARPAS422 cell growth with an IC50 value of 1.2 nM. It achieves an excellent PK and ADME profile and its oral administration leads to complete and persistent tumor regression in the KARPAS422 xenograft model in mice at well-tolerated dose schedules. Co-crystal structures of two potent EED inhibitors with EED provide a solid structural basis for their high-affinity binding. Collectively, UM-EEDi-5273 represents a highly promising EED inhibitor for further advanced preclinical development for the treatment of human lymphoma and other types of human cancer in which the PRC2 complex activity may play a key role.

UM-EEDi-5273, an exceptionally potent, and orally efficacious EED inhibitor capable of achieving complete and persistent tumor regression

ACS Spring 2022

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