# Development of a potent and selective oral ENPP1 inhibitor for oncology

> **NIH NIH R44** · STINGRAY THERAPEUTICS, INC. · 2022 · $1,160,011

## Abstract

ABSTRACT
Compelling evidence suggests that careful and therapeutically relevant activation of the STING (STimulator of
INterferon Genes) pathway is necessary to elicit potent anti-cancer innate immune responses. Ectonucleotide
pyrophosphatase/phosphodiesterase 1 (ENPP1) is the STING pathway's only known direct negative regulator
expressed in many tumor types, and, when it is overexpressed, tumors show limited efficacy to front-line
therapies. Such as, in triple-negative breast cancer (TNBC), high ENPP1 expression is associated with drug
resistance and poor prognosis. If a safe and efficacious ENPP1 inhibitor were available, it would have
widespread utility for multiple cancer types and, if used in combination with other cancer therapies, may enhance
their performance. Towards this end, we have developed an orally bioavailable potent small-molecule inhibitor
of ENPP1 called SR-8541A. It inhibits hENPP1 activity with an IC50 of 3.6 nM (Ki=1.9 nM) and demonstrates
robust selectivity. We have established that it activates the STING pathway, promotes immune cell infiltration,
and inhibits cancer spheroid growth. Furthermore, in syngeneic tumor mouse models, SR-8541A demonstrates
a synergistic effect with radiation, and a preliminary study also shows synergy with checkpoint inhibitors. To
date, we have completed preclinical development activities on SR-8541A that include API development and
manufacturing, stability, pharmacokinetics, tolerability, and preliminary toxicology (mouse, rat, dog). The overall
goal of this Direct to Phase II SBIR application is to complete non-GLP and GLP preclinical studies for our lead
molecule SR-8541A with TNBC as our initial focus. In Aim 1, we will evaluate the efficacy of SR-8541A in
combination with FDA-approved drug regimens (e.g., cisplatin, anti-mCTLA-4, anti-mPD-1, PARP inhibitor) in
4T-1 and EMT-6 breast cancer mouse models. In Aim 2, we will conduct IND enabling GLP toxicology study in
dogs as the rat GLP study is complete. In Aim 3, we will develop and manufacture cGMP clinical-grade tablets
necessary to conduct a Phase 1 clinical trial. Direct to Phase II SBIR success will result in the completion of the
required preclinical studies to seek IND acceptance for a first-in-human Phase I clinical trial and to engage with
private-sector investors in funding clinical trials in TNBC. If SR-8541A is approved for patient use, it would be
the first-in-class molecule to modulate the innate immune system, expanding the benefits of immunotherapy to
more patients.

## Key facts

- **NIH application ID:** 10603980
- **Project number:** 1R44CA278144-01
- **Recipient organization:** STINGRAY THERAPEUTICS, INC.
- **Principal Investigator:** Mohan Rao Kaadige
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,160,011
- **Award type:** 1
- **Project period:** 2022-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10603980

## Citation

> US National Institutes of Health, RePORTER application 10603980, Development of a potent and selective oral ENPP1 inhibitor for oncology (1R44CA278144-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10603980. Licensed CC0.

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