# Development of Notch1-selective Small Molecule Inhibitor for the Treatment of Cancer

> **NIH NIH R44** · STEMSYNERGY THERAPEUTICS, INC. · 2022 · $1,030,992

## Abstract

ABSTRACT
The incidence of esophageal adenocarcinoma (EAC) has tripled over the last 40 years, but five-year overall
survival is still poor due to late stage diagnosis, metastasis, and high rates of recurrence after standard
chemotherapy. Standard-of-care therapy (neoadjuvant chemotherapy, radiation, or both followed by
esophagectomy) achieves only 20% response rates, while 80% of patients remain poorly responsive. Recently,
we have shown that aberrant activation of Notch1 signaling correlates with poor therapeutic responses and
outcomes in EAC patients and that EAC tumors are dependent upon sustained Notch1 activity. The vast majority
of R&D efforts to inhibit Notch have focused on gamma secretase inhibitors (GSIs), which inhibit all Notch
proteins, and as a result cause significant dose-limiting toxicity, largely hampering their clinical utility to date.
Thus, there is a significant unmet clinical need for targeted therapies against Notch1-dependent cancers such
as EAC. StemSynergy Therapeutics has identified a first-in-class inhibitor series that binds and inhibits the
Notch1 Transcriptional Complex and limits transcription of downstream effectors of Notch1 signaling. We have
demonstrated that only Notch1-dependent EAC cell lines are sensitive to our inhibitors, which blocked the growth
of EAC patient-derived xenograft tumors. We further improved pharmacokinetics and specificity to produce our
lead clinical candidate SSTN-302, which is a highly potent and selective inhibitor of Notch1 and inhibits EAC
tumor growth in vivo. Furthermore, SSTN-302 has promising ADME properties, high oral bioavailability, and most
importantly - avoids the dose-limiting toxicity of GSIs. This Direct Phase II proposal seeks to determine the
preclinical safety of SSTN-302 for the purposes of advancing a novel Notch1 inhibitor into the clinic.

## Key facts

- **NIH application ID:** 10478196
- **Project number:** 5R44CA261490-02
- **Recipient organization:** STEMSYNERGY THERAPEUTICS, INC.
- **Principal Investigator:** Dennis Liang Fei
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,030,992
- **Award type:** 5
- **Project period:** 2021-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10478196

## Citation

> US National Institutes of Health, RePORTER application 10478196, Development of Notch1-selective Small Molecule Inhibitor for the Treatment of Cancer (5R44CA261490-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10478196. Licensed CC0.

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