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Updated: Jun 16, 2026
Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
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.
Abstract:
Overexpression and somatic heterozygous mutations of EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2), are associated with several tumor types. EZH2 inhibitor, EPZ-6438 (tazemetostat), demonstrated clinical efficacy in patients with acceptable safety profile as monotherapy. EED, another subunit of PRC2 complex, is essential for its histone methyltransferase activity through direct binding to trimethylated lysine 27 on histone 3 (H3K27Me3). Herein we disclose the discovery of a first-in-class potent, selective, and orally bioavailable EED inhibitor compound 43 (EED226). Guided by X-ray crystallography, compound 43 was discovered by fragmentation and regrowth of compound 7, a PRC2 HTS hit that directly binds EED. The ensuing scaffold hopping followed by multiparameter optimization led to the discovery of 43. Compound 43 induces robust and sustained tumor regression in EZH2MUT preclinical DLBCL model. For the first time we demonstrate that specific and direct inhibition of EED can be effective as an anticancer strategy.
Insights
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.
