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 catalyzesmethylation of histone H3 lysine 27 (H3K27), resulting in mono-,di-, or trimethylated forms of H3K27, of which the trimethylatedform H3K27me3 leads to transcriptional repression of polycombtarget genes. Previously, we have shown that binding of the low-molecular-weight compound EED226 to the H3K27me3 bindingpocket of the regulatory subunit EED can effectively inhibit PRC2activity in cells and reduce tumor growth in mouse xenograftmodels. Here, we report the stepwise optimization of the tool compound EED226 toward the potent and selective EED inhibitorMAK683 (compound22) 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

Automated summary

PRC2 plays a crucial role in animal development and cell differentiation, and its alteration has been linked to cancer. The compound EED226 has shown potential to inhibit PRC2 activity and reduce tumor growth.