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Discovery of the Clinical Candidate MAK683: An EED-Directed, Allosteric, and Selective PRC2 Inhibitor for the
Ying Huang1, Martin Sendzik2,3, Jeff Zhang1
1Novartis Institutes for BioMedical Research, 4218 Jinke Road, Shanghai 201203, China.
Abstract:
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.
Insights
Researchers optimized EED226, a Polycomb Repressive Complex 2 (PRC2) inhibitor, into MAK683. This potent and selective inhibitor shows promise for cancer therapy due to its efficacy and safety profile.
Area of Science:
- Biochemistry
- Molecular Biology
- Epigenetics
Background:
- Polycomb Repressive Complex 2 (PRC2) is crucial for transcriptional regulation in development and differentiation.
- Aberrant PRC2 activity is linked to various cancers.
- PRC2 catalyzes histone H3 lysine 27 methylation (H3K27me3), leading to gene silencing.
Purpose of the Study:
- To optimize the tool compound EED226 into a potent and selective inhibitor of PRC2.
- To conduct preclinical characterization of the optimized compound, MAK683.
- To evaluate MAK683 for potential clinical development as a cancer therapeutic.
Main Methods:
- Stepwise chemical optimization of EED226.
- Biochemical and cellular assays to assess PRC2 inhibition.
- Pharmacokinetic/pharmacodynamic (PK/PD) profiling.
- Preclinical efficacy studies in mouse xenograft models.
- Metabolite profiling to assess safety.
Main Results:
- Development of MAK683, a potent and selective EED inhibitor targeting PRC2.
- MAK683 demonstrated significant tumor growth inhibition in preclinical models.
- MAK683 exhibits a balanced PK/PD profile.
- Minimized risk of reactive metabolite formation was observed.
Conclusions:
- MAK683 represents a promising drug candidate for PRC2-driven cancers.
- The optimized inhibitor possesses favorable efficacy and safety characteristics for clinical advancement.
- MAK683 is selected for clinical development based on its preclinical profile.
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