# Small Molecule Inhibitors of Notch Activation Complex Kinase (NACK) as Novel Cancer Therapeutic Agents

> **NIH NIH R43** · STEMSYNERGY THERAPEUTICS, INC. · 2020 · $399,999

## Abstract

ABSTRACT
Aberrantly activated NOTCH signaling contributes to tumorigenesis in a range of cancer types, including
esophageal adenocarcinoma (EAC), the incidence of which has tripled over the last 40 years with poor overall
five-year survival. The Notch Activation Complex Kinase (NACK) is a co-activator of NOTCH signaling, and is
often overexpressed in NOTCH-dependent cancers. Genetic depletion of NACK is effective in eradicating
NOTCH-dependent EACs in pre-clinical models, suggesting that NACK is a promising therapeutic target for
NOTCH-dependent cancers. Through a licensing agreement with University of Miami, we have obtained
exclusive rights to develop small molecules targeting the NACK kinase domain (iNACKs), in order to treat
NOTCH/NACK-dependent cancers. So far, we have developed several iNACKs that prevent NACK from being
recruited to the NOTCH transcriptional complex, inhibit NOTCH pathway activation, and suppress the growth
of NOTCH/NACK-dependent EAC in cell culture and in mice. Moreover, we show that our early lead iNACK
does not elicit gastrointestinal track (GI) toxicity, which is often associated with NOTCH blockage by gamma
secretase inhibitors. Therefore, we hypothesize that blockade of NOTCH signaling via inhibition of NACK will
be safe and effective in NOTCH-dependent cancers.
The goal of our proposal is to develop next-generation iNACKs, that are more potent, specific, and possess
better drug-like properties. We propose two specific aims:
A1. Develop iNACKs with improved potency, selectivity, and pharmacokinetic properties through Structure-
Activity Relationship (SAR) studies.
A2. Evaluate the drug-like properties and in vivo efficacy of SSTK-0388 and other iNACKs through ADMET,
pharmacokinetics (PK), and mouse xenograft studies.
These aims will establish up to two lead iNACK compounds for further development, including: (1) Efficacy in
more human patient-derived xenografts and genetically engineered tumor models, which are NOTCH-
dependent; (2) Efficacy in targeting a self renewing (“cancer stem cell”) population; (3) Potential cancer
resistant mechanisms following NACK blockage; (4) Comprehensive pharmacokinetics and toxicology
analyses in a future Phase II SBIR application. The clinical and market potential of a NACK-targeted NOTCH
inhibitor for cancer treatment is enormous and fulfill a significant unmet need in patients.

## Key facts

- **NIH application ID:** 10010409
- **Project number:** 1R43CA246945-01A1
- **Recipient organization:** STEMSYNERGY THERAPEUTICS, INC.
- **Principal Investigator:** Dennis Liang Fei
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $399,999
- **Award type:** 1
- **Project period:** 2020-05-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10010409

## Citation

> US National Institutes of Health, RePORTER application 10010409, Small Molecule Inhibitors of Notch Activation Complex Kinase (NACK) as Novel Cancer Therapeutic Agents (1R43CA246945-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10010409. Licensed CC0.

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