# Development of a new class of EZH2 inhibitors in ERa-negative breast cancer.

> **NIH NIH R21** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2024 · $86,717

## Abstract

PROJECT SUMMARY/ABSTRACT
 The histone methyltransferase (HMTase) EZH2 was proved to drive malignant phenotypes in various types
of cancer cells, including the estrogen receptor a-negative (ERa-) breast cancer. Therefore, selective small-
molecule inhibitors of EZH2 have been developed, all of which block its enzymatic activity. However,
accumulating evidence suggests that HMTase activity of EZH2, which is executed by the C-terminal
catalytic SET domain, may not represent an ideal target for anticancer drugs in certain situations. First,
multiple genetic studies suggest that the HMTase activity of EZH2 plays a tumor suppressive role in some types
of cancer. Second, EZH2 may promote tumorigenesis and cancer progression independent of its HMTase
competence. These scientific discoveries explain why some cancer cells that require EZH2 for their tumorgenicity
are insensitive to current EZH2 inhibitors and why secondary malignances were sometimes noted in patients
receiving tazemetostat, the first FDA-approved HMTase inhibitor of EZH2. All these clinical failures warrant the
development of new EZH2 inhibitors blocking the HMTase-independent oncogenic function of EZH2,
which may exhibit stronger antitumor potency, fewer side effects and wider clinical applications.
 Recently, an N-terminal transactivation domain (TAD) was found to mediate the tumor-promoting effect of
EZH2 via gene activation instead of the HMTase activity. In ERa- breast cancer cells, we demonstrated that
malignant phenotypes such as proliferation and migration were unaffected upon tazemetostat treatment or
overexpression of the SET domain-deleted EZH2 but dramatically hindered when the TAD domain was truncated
or when the critical residues for the proper protein folding of the TAD domain were mutated. More importantly, a
group of genes that are essential for tumor migration was specifically activated by the functional TAD domain,
but not regulated by the SET domain. All these results suggest that this particular N-terminal TAD domain, rather
than the methyltransferase activity that current EZH2 inhibitors block, is required for the oncogenic function of
EZH2 in ERa- breast cancer cells. Based on these findings, we carried out a high-throughput screening for
chemicals that specifically interact with this TAD domain and a candidate compound was thus identified. The
lead compound directly binds to the TAD domain of EZH2, downregulates genes that promote cancer
cell migration and abrogates the aggressive phenotypes of ERa- breast cancer cells without interfering
with the methyltransferase activity of EZH2. Computer-aided structural analysis suggests that the critical
residues essential for the structure and functionality of the TAD domain may directly interact with this
prototype compound. Based on these preliminary data, we aim to develop a new class of EZH2 inhibitors
that target the N-terminal TAD domain and to further characterize their chemical and biological features
in the proposed ...

## Key facts

- **NIH application ID:** 10785225
- **Project number:** 1R21CA277399-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Kexin Xu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $86,717
- **Award type:** 1
- **Project period:** 2024-01-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10785225

## Citation

> US National Institutes of Health, RePORTER application 10785225, Development of a new class of EZH2 inhibitors in ERa-negative breast cancer. (1R21CA277399-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10785225. Licensed CC0.

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