# Novel NFAT1-MDM2 inhibitor for Breast Cancer Therapy

> **NIH NIH R01** · UNIVERSITY OF HOUSTON · 2020 · $578,917

## Abstract

The long-term objective of this project is to develop a novel dual-targeting therapeutic strategy (MDM2 and
NFAT1) for the treatment of advanced breast cancer. Patients with advanced breast cancer, especially those
with triple negative breast cancer (TNBC), cannot benefit from the recently-developed targeted therapies.
Accumulating evidence has demonstrated that the dysfunction of several key signaling pathways, including
NFAT1-MDM2 pathway, is associated with a poor prognosis and chemo-/radio-resistance, providing novel
molecular targets for breast cancer therapy. The MDM2 oncogene is a major negative regulator of p53 and
also has p53-independent oncogenic activity. It has been suggested to be a valid molecular target for breast
cancer therapy. To date, the majority of small molecule inhibitors (SMIs) of MDM2 have been designed to
block the binding of MDM2 to p53, and their anticancer activity was therefore dependent on the expression of
wild-type p53 in the cancer cells. However, the majority of TNBC harbors mutant p53 and has high levels of
MDM2, so the existing MDM2 SMIs are expected to have low or no efficacy against this subtype of breast
cancer. Therefore, it is highly desirable to discover and develop novel MDM2 inhibitors that have direct effects
on MDM2 and exert their anticancer activity independent of the p53 status of the cancer cells. The activation of
NFAT1 is also commonly observed in breast cancers, especially in TNBC, promoting the development of an
invasive, high-grade, and late-stage tumor phenotype. Therefore, the applicants propose NFAT1 as a novel
target for the development of anti-breast cancer agents. Thus far, there has been no specific NFAT1 inhibitors
developed for cancer therapy. Specific to this proposal, the applicants have recently discovered that NFAT1
up-regulates MDM2 expression and contributes to MDM2 overexpression in cancer cells and cancer tissues,
including breast cancer. Based on newly-generated preliminary data, the applicants propose simultaneously
targeting NFAT1 and MDM2 as a promising therapeutic strategy for advanced breast cancer. The applicants
have recently accomplished a high-throughput screening of a natural product-based library, and have identified
a series of disesquiterpenoid candidates with potent inhibitory effects on both NFAT1 and MDM2. One of the
lead compounds, Japonicone A (JapA), has shown significant in vitro activity, in vivo efficacy, and minimal host
toxicity in breast cancer models. Mechanistically, JapA directly binds to the MDM2 and NFAT1 proteins with
high affinity, and induces MDM2 and NFAT1 protein instability. It also inhibits NFAT1-mediated MDM2
transcription by disrupting the binding of NFAT1 to the MDM2 P2 promoter. This first-in-class MDM2 inhibitor is
distinct from all of the existing MDM2 inhibitors. In this revised proposal, the applicants will use JapA as a lead
compound to test the central hypothesis that the dual targeting MDM2 and NFAT1 represents an effective a...

## Key facts

- **NIH application ID:** 9991772
- **Project number:** 5R01CA214019-04
- **Recipient organization:** UNIVERSITY OF HOUSTON
- **Principal Investigator:** RUIWEN ZHANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $578,917
- **Award type:** 5
- **Project period:** 2017-09-04 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991772

## Citation

> US National Institutes of Health, RePORTER application 9991772, Novel NFAT1-MDM2 inhibitor for Breast Cancer Therapy (5R01CA214019-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9991772. Licensed CC0.

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