# Development of chemical probe targeting NSD3 SET domain in breast cancer

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $572,327

## Abstract

Abstract
Epigenetic abnormalities are common in human cancers and play a critical role in tumorigenesis via
dysregulation of gene expression and by affecting chromatin function. Nuclear receptor binding SET domain
protein 3 (NSD3/WHSC1L1) belongs to the family of NSD histone methyltransferases that catalyze mono- and
di-methylation of lysine 36 on histone H3 (H3K36me1/2). NSD3 gene is located within 8p11-12 region
amplified in approximately 15% of patients with breast carcinomas and this amplification is significantly
associated with disease-specific survival and distant recurrence in breast cancer patients. NSD3 has been
identified as a key oncogenic driver within 8p11-12 amplicon and knockdown of NSD3 results in profound loss
of growth and survival of breast cancer cells. However, NSD3 is a complex and multidomain protein, and
despite multiple efforts, no studies unambiguously validated whether the catalytic SET domain is essential for
the oncogenic activity of NSD3. Here, we propose to assess the importance of the NSD3 SET domain in
oncogenesis by developing small molecule chemical probes. This approach is highly novel as no NSD3
inhibitors targeting catalytic SET domain were reported in the literature. To date, we identified a class of small
molecule compounds that bind selectively to the NSD3 SET domain, but not to the closely related NSD1 or
NSD2. In preliminary studies, our inhibitors specifically block growth of breast cancer cells with amplifications
of NSD3. The goal of this proposal is to further develop these compounds and validate whether optimized
chemical probes blocking catalytic activity of NSD3 would impair development and progression of breast
cancer in vivo. To accomplish this goal, we will employ extensive medicinal chemistry to improve potency,
selectivity and pharmacokinetic properties of our NSD3 inhibitors. Efficacy of the most potent compounds will
be evaluated in xenograft and PDX models of breast cancer. We are confident that our comprehensive plan
will lead to successful development of potent NSD3 chemical probes for exploration of NSD3 biology in breast
cancer and other tumors with 8p11-12 amplifications.

## Key facts

- **NIH application ID:** 10772406
- **Project number:** 1R01CA285304-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Tomasz Cierpicki
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $572,327
- **Award type:** 1
- **Project period:** 2024-03-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10772406

## Citation

> US National Institutes of Health, RePORTER application 10772406, Development of chemical probe targeting NSD3 SET domain in breast cancer (1R01CA285304-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10772406. Licensed CC0.

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