Discovery of the Clinical Candidate MAK683: An EED-Directed, Allosteric, and Selective PRC2 Inhibitor for the Treatment of Advanced Malignancies

Polycomb
Repressive Complex 2 (PRC2) plays an important role in
transcriptional regulation during animal development and in cell differentiation,
and alteration of PRC2 activity has been associated with cancer. On
a molecular level, PRC2 catalyzes methylation of histone H3 lysine
27 (H3K27), resulting in mono-, di-, or trimethylated forms of H3K27,
of which the trimethylated form H3K27me3 leads to transcriptional
repression of polycomb target genes. Previously, we have shown that
binding of the low-molecular-weight compound EED226 to the H3K27me3
binding pocket of the regulatory subunit EED can effectively inhibit
PRC2 activity in cells and reduce tumor growth in mouse xenograft
models. Here, we report the stepwise optimization of the tool compound
EED226 toward the potent and selective EED inhibitor MAK683 (compound 22) and its subsequent preclinical characterization. Based
on a balanced PK/PD profile, efficacy, and mitigated risk of forming
reactive metabolites, MAK683 has been selected for clinical development.