# Dissecting and targeting canonical and non-canonical oncogenic functions of EZH2 in cancer

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $643,960

## Abstract

PROJECT SUMMARY/ABSTRACT
Leukemia patients bearing MLL1 rearrangement generally display very poor prognosis, demanding new
treatment strategies. Multiple independent studies have identified EZH2, a histone methyltransferase and
catalytic subunit of Polycomb Repressive Complex 2 (PRC2), as an attractive drug target in MLL1-rearranged
leukemias. However, the current catalytic inhibitors of EZH2 have limited anti-tumor effect. Our preliminary
studies show that EZH2 also binds c-MYC and has a non-canonical function in activation of oncogenes (such
as Cyclin E1) in MLL1-rearranged leukemias, which differs from the well-known PRC2:EZH2-driven canonical
function related to gene repression. In order to target both canonical and non-canonical oncogenic actions by
EZH2, we used the Proteolysis Targeting Chimera (PROTAC) technology to generate novel EZH2 small-
molecule degraders including MS177. Our extensive preliminary studies have demonstrated that MS177
effectively degrades both PRC2:EZH2 and non-PRC2 partners of EZH2 (e.g., c-MYC, which binds EZH2 to
activate oncogenes), thus suppressing both canonical and non-canonical oncogenic activities of EZH2 in
tumor. Importantly, our preliminary results also show that MS177 is superior to all of enzymatic inhibitors of
EZH2 in treating MLL1-rearranged leukemias. Thus, we hypothesize that: (1) EZH2 has a less-studied, non-
canonical oncogenic function, which acts in parallel with the PRC2:EZH2-dependent one to produce more
aggressive tumor phenotypes seen in MLL1-rearranged leukemias; and (2) targeting both canonical and non-
canonical activities of EZH2 by PROTACs represents a novel and superior therapeutic strategy to inhibition of
EZH2’s enzymatic activity alone. Dissection of the mechanisms underlying EZH2-mediated oncogenesis and
development of an optimal EZH2 PROTAC as a drug candidate will have significant impact on improving
treatments for MLL1-rearranged leukemia patients. Towards this goal, we will further characterize such a new
non-canonical oncogenic role of EZH2 in MLL1-rearranged leukemias (Aim 1a) and define effects of EZH2
PROTACs on suppressing both canonical and non-canonical oncogenic activities of EZH2 (Aim 1b). We will
also determine in vitro and vivo therapeutic effects of EZH2 PROTACs by employing multiple independent
MLL1-rearranged leukemia models including human/murine cancer cells and patient-derived xenografts (PDX)
(Aim 2). Lastly, we will optimize our EZH2 PROTAC leads into a drug candidate (Aim 3). Completion of the
proposed research will not only provide novel mechanistic understanding of how MLL1-rearranged leukemias
develop, but will also validate an innovative therapeutic strategy and deliver a promising therapeutic candidate
for the treatment of affected cancer patients.

## Key facts

- **NIH application ID:** 10389877
- **Project number:** 1R01CA268519-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Jian Jin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $643,960
- **Award type:** 1
- **Project period:** 2022-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10389877

## Citation

> US National Institutes of Health, RePORTER application 10389877, Dissecting and targeting canonical and non-canonical oncogenic functions of EZH2 in cancer (1R01CA268519-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10389877. Licensed CC0.

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