# Identification of Small Molecule Inhibitors of QSOX1

> **NIH NIH R43** · SAPPHIRE BIOTECH, INC. · 2020 · $395,880

## Abstract

Identification of Small Molecules that inhibit QSOX1
Project Summary
 The Quiescin Sulfhydryl Oxidase 1 (QSOX1) enzyme is over-produced by multiple types of tumors
including pancreas, breast, kidney, lung and prostate. QSOX1 shuttles disulfide bonds in proteins while
they are folding in the ER and Golgi. It is especially active in the extracellular matrix (ECM) where it plays
a role in tumor cell invasion by helping to fold proteins involved in adherence (laminin) and matrix
metalloproteinases. We first targeted QSOX1 by genetically silencing its expression (shRNA) which
suppressed tumor growth, invasion and metastasis in vitro and in vivo. This led to the hypothesis that
small molecules might also inhibit the enzyme resulting in similar anti-tumor activities.
 High throughput screening identified several chemical compounds that inhibit the enzymatic
activity of QSOX1. The first reported compound was ebselen, a selenium-containing molecule that was
shown to covalently bind to Cys-165 and Cys-237 on QSOX1. Treatment of mice bearing human tumor
xenografts with ebselen demonstrated suppression of tumor cell growth and invasion compared to
controls. Although ebselen was active and inhibited QSOX1, it is somewhat non-specific and also inhibits
other enzymes.
 The second compound, SBI-183, i) inhibits the enzymatic activity of QSOX1 in a cell free assay,
ii) binds to QSOX1 with a Kd of 20uM and iii) suppresses tumor cell invasion and metastasis in vitro and
in a human tumor xenograft model. Maximal tolerated dose (MTD) studies in mice were >200mg/kg and
revealed no pathology in vital organs such as heart, lungs, kidney, and liver. The anti-tumor activity of
SBI-183 suggests that identifying more potent analogs of SBI-183 may be useful in the development of
anti-tumor/metastatic compounds against QSOX1 as a novel target. This phase I SBIR proposal will
employ medicinal chemistry techniques to screen analogs of SBI-183 using a screening funnel that
includes i) QSOX1 enzyme inhibition assays, ii) binding assays and iii) in vitro tumor cell invasion assays.
Three to five analogs will be identified that will move forward for testing in human xenograft models in a
phase II project that includes adsorption, distribution, metabolism, excretion and toxicity (ADMET) studies.

## Key facts

- **NIH application ID:** 10080811
- **Project number:** 1R43CA250719-01A1
- **Recipient organization:** SAPPHIRE BIOTECH, INC.
- **Principal Investigator:** Sergei Svarovsky
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $395,880
- **Award type:** 1
- **Project period:** 2020-08-05 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10080811

## Citation

> US National Institutes of Health, RePORTER application 10080811, Identification of Small Molecule Inhibitors of QSOX1 (1R43CA250719-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10080811. Licensed CC0.

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