Inhibition of PRC2 activity via an allosteric mechanism offers a promising new therapeutic strategy for treatment of PRC2-dependent cancers. We have designed a new class of EED inhibitors using structure-based design approach. Our efforts have yielded a series of highly potent and orally active EED inhibitors, as exemplified by UM-EEDi-5285. UM-EEDi-5285 binds to EED protein with a low nanomolar affinity and achieves IC<sub>50</sub> values of &lt; 1 nM in inhibition of cell growth in Pfeiffer and Karpas-422 lymphoma cell lines carrying an EZH2 mutation. UM-EEDi-5285 is capable of achieving complete and durable tumor regression in the KARPAS-422 xenograft model in mice at well-tolerated dose-schedules. The co-crystal structure of UM-EEDI 5285 in a complex with EED provides the structural basis for their high-affinity interaction. Taken together, our data show that UM-EEDi-5285 is arguably the most potent and efficacious EED inhibitor reported to date. UM-EEDi-5285 is a highly promising lead compound for advanced preclinical development studies for the treatment of human cancer.<br/>

Structure-based discovery of a highly potent and orally active small-molecule inhibitor of embryonic ectoderm development (EED) capable of achieving complete tumor regression

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.