# EZH2 in cancer biology and novel inhibitors

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2021 · $536,827

## Abstract

Enhancer of zeste 2 (EZH2), a histone methyl transferase subunit of the Polycomb Repressive Complex 2
(PRC2), catalyzes the methylation of lysine residue 27 on histone 3 (H3K27). Methylation of H3K27 inhibits the
transcription of nearby genes by blocking the recruitment of the proteins necessary for gene activation. The
PRC2 complex and the histone modifications that it regulates are tightly controlled in normal cells but can
become dysregulated in cancer to aberrantly activate or repress gene expression. Over the last decade, many
independent studies have established that EZH2 is highly expressed in numerous cancers and recurrently
mutated in several others. Overexpression of EZH2 is associated with aggressive progression and poor
prognosis. We recently demonstrated that overexpression of EZH2 is causative of lung adenocarcinoma in
mice. Likewise, activating somatic mutations of EZH2 have been identified in B cell lymphoma and malignant
melanoma. We developed mouse models to express the gain-of-function mutant of EZH2 in B cells or
melanocytes, which caused high-penetrance lymphoma or melanoma, respectively. Our studies with mouse
models that express the gain-of-function mutant of EZH2 suggest that EZH2Y641F induces lymphoma and
melanoma through a vast reorganization of chromatin structure inducing both repression and activation of
PRC2-regulated loci. The extensive evidence linking EZH2 activity to cancer has prompted interest in the
underlying biological mechanisms, including the link to the tumor immune environment.
As such, we developed a novel EZH2 small molecule inhibitor, JQEZ5, that can efficiently block the enzymatic
function of both wild-type and mutant EZH2 and reduce the methylation of H3K27. The inhibitory activity of
JQEZ5 impedes the growth of cancer cells in culture and in mouse models of lung cancer, lymphoma and
melanoma. Mechanistically, JQEZ5 is a non-covalent inhibitor that competes off natural co-factor S-adenosine
methionine (SAM) from binding with EZH2. The SAM-competitive nature of all current EZH2 inhibitors largely
limited their in vivo potency, which could potentially limit their usage in cancer therapy.
To improve the in vivo efficacy of EZH2 inhibitors and reduce off-target toxicity, we propose to develop and
characterize a new class of covalent EZH2 inhibitors that can irreversibly bind to unique cysteine residue (C663)
present in human and mouse EZH2. We hypothesize that the irreversible biding of this new class inhibitors can
overcome key limitations of the existing non-covalent inhibitors, and improve in vivo potency and selectivity. We
will employ the new covalent EZH2 inhibitors to further investigate cancer biology of EZH2 inhibition in lung
cancer, including the immunomodulatory effects of EZH2 inhibition. We will utilize our cell culture and mouse
models of EZH2-driven cancer to explore the impact of irreversible inhibition of EZH2 on gene expression and
the tumor immune microenvironment while driving hit-t...

## Key facts

- **NIH application ID:** 10224685
- **Project number:** 5R01CA222218-04
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Jun QI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $536,827
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10224685

## Citation

> US National Institutes of Health, RePORTER application 10224685, EZH2 in cancer biology and novel inhibitors (5R01CA222218-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10224685. Licensed CC0.

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