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Discovery of First-in-Class, Potent, and Orally Bioavailable Embryonic Ectoderm Development (EED) Inhibitor with
Ying Huang1, Jeff Zhang1, Zhengtian Yu1
1Novartis Institutes for BioMedical Research , 4218 Jinke Road, Shanghai 201203, China.
Journal of Medicinal Chemistry
|January 17, 2017
Summary
Researchers discovered a new drug, EED226, that directly inhibits EED, a key part of the PRC2 complex. This novel EED inhibitor shows promise for treating cancers driven by EZH2 mutations.
Area of Science:
- Oncology
- Epigenetics
- Drug Discovery
Background:
- EZH2 mutations and overexpression are linked to various cancers.
- EZH2 inhibitors like tazemetostat show clinical efficacy.
- EED is crucial for PRC2 complex activity, binding to H3K27Me3.
Purpose of the Study:
- To discover and characterize a novel, potent, selective, and orally bioavailable inhibitor of EED.
- To evaluate the anticancer potential of direct EED inhibition.
Main Methods:
- Fragment-based drug discovery utilizing X-ray crystallography.
- Lead optimization through scaffold hopping and multiparameter refinement.
- Preclinical testing in an EZH2-mutant Diffuse Large B-cell Lymphoma (DLBCL) model.
Main Results:
- Discovery of compound 43 (EED226), a first-in-class EED inhibitor.
- Compound 43 demonstrated potent and selective inhibition of EED.
- EED226 induced significant tumor regression in preclinical models.
Conclusions:
- Direct EED inhibition represents a viable anticancer strategy.
- EED226 is a promising therapeutic candidate for EZH2-mutant cancers.
- This study validates EED as a direct therapeutic target.
