# Targeting histone methyltransferase EZH2 for the treatment of hematological cancer

> **NIH NIH F32** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $71,734

## Abstract

PROJECT SUMMARY & ABSTRACT
Enhancer of Zeste Homolog 2 (EZH2), the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), induces
trimethylation of histone H3 lysine 27 (H3K27me3) for repressing the target gene expression. Numerous studies
have reported that EZH2 promotes oncogenesis in a range of human cancers. In particular, independent studies
have demonstrated the expression of EZH2 to be essential for tumorigenicity of acute leukemias with the Mixed
Lineage Leukemia gene rearrangement (MLL-r), which accounts for approximately 60–80% of infantile and
~10% of adult acute lymphoblastic leukemia (ALL) cases, as well as ~50% of infantile and ~7% of adult acute
myeloid leukemia (AML) cases. Leukemia patients with MLL-r generally exhibit very poor prognosis in the clinic,
demanding new treatment strategies. However, increasing evidence including ours now support that EZH2’s
oncogenic functions go beyond PRC2 and its enzymatic function for H3K27me3 deposition, and has the new,
PRC2-independent activity (non-canonical) to sustain oncogenesis. The latter non-canonical function of EZH2
partly explains why the current existing enzymatic inhibitors of EZH2 have rather limited antitumor effect. In this
project, we aim to employ the Proteolysis Targeting Chimera (PROTAC) technology to develop novel
pharmacological ‘degraders’ for depleting EZH2 functions in cancer as a new and more effective
therapeutic agent. We have generated highly promising preliminary results showing that, compared to the EZH2
enzymatic inhibitor, our lead E3 ligase-based EZH2-targeting PROTAC (aka EZH2 degrader) efficiently induced
depletion of EZH2, thereby suppressing both canonical (PRC2-dependent) and non-canonical (PRC2-
independent) activities of EZH2 in tumor. The EZH2 degrader also displays a much stronger potency in killing
the aggressive MLL-r AML cells in vitro. Additionally, preliminary characterization of this lead compound revealed
an excellent drug-like potential in mice. In this project, I will further (i) determine the effect and potency of our
EZH2 degrader in suppressing tumor growth in vivo by using the genetically engineered mouse model (GEMM)
and human patient-derived xenograft (PDX) models of MLL-r leukemias (Aim 1) and (ii) define its molecular
effects in the MLL-r leukemia cells, focusing on both canonical and non-canonical functions of EZH2, by using
the integrated genomic profiling technologies (Aim 2). Results from this project will reveal a promising preclinical
strategy for the treatment of human cancers showing EZH2 dependency. Recent FDA approval of compounds
targeting epigenetic proteins makes a strong argument.

## Key facts

- **NIH application ID:** 10387358
- **Project number:** 1F32CA261118-01A1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** A-Rum Kim
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $71,734
- **Award type:** 1
- **Project period:** 2022-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10387358

## Citation

> US National Institutes of Health, RePORTER application 10387358, Targeting histone methyltransferase EZH2 for the treatment of hematological cancer (1F32CA261118-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10387358. Licensed CC0.

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