# Discovering hybrid inhibitors for tumor microenvironment disruption

> **NIH NIH R21** · TUFTS UNIVERSITY MEDFORD · 2020 · $188,150

## Abstract

Although cancer-promoting activities of extracellular proteases and peptidases in the tumor
microenvironment are well known, the specific disruption of a single enzyme in basic and translational settings
remains a fundamental challenge. For example, the use of pan-specific chemical inhibitors of matrix
metalloproteinases (MMPs) in animal models of cancer has demonstrated that interfering with MMP activity
can slow cancer progression, but clinical translation of these inhibitors has failed, largely due to lack of inhibitor
specificity. Efforts to discover specific inhibitors or rapidly implement genetic approaches to interfere with
MMPs and other enzymes active in the tumor microenvironment remain challenging. Emerging findings
indicate that MMPs modulate signaling and immune function in the tumor microenvironment, making highly
specific reagents critical to elucidate the wide range of roles MMPs play within the tumor microenvironment
and to establish a new generation of inhibitors for potential clinical applications.
 In this application, we propose to establish a platform for the discovery of highly specific enzyme inhibitors
in high throughput. Our underlying technology combines the use of yeast display and noncanonical amino
acids to construct and evaluate inhibitors with structures that are not accessible using conventional
approaches. We hypothesize that precisely positioning small molecules within an antibody framework will yield
bivalent “hybrid inhibitors” that retain antigen specificity while gaining potent inhibitory capabilities. We will
implement our yeast-based discovery platform by targeting MMP-2, -7, -9, and -14 because of the availability
of numerous MMP-related tools that will allow us to explore the capabilities of our platform. We will establish
our platform using the following two specific aims: 1) Identify effective small molecule positioning in antibodies
to enable efficient hybrid discovery. In this Aim, we will quantitatively explore the effects of small molecule
attachment sites, functional groups, and linkers within antibody variable regions to identify the most promising
combinations of these factors for large-scale hybrid discovery. 2) Establish quantitative relationships between
inhibitor properties and cell invasion. In this Aim, we will compare data we derive from yeast-based
measurements with data from standard biochemical and cell-based assays in order to set numerical targets
during hybrid discovery efforts and to examine the roles of MMPs in cell invasion.
 The platform proposed here will yield molecular reagents with structures and specificities that cannot be
accessed using existing small molecule- or protein-based approaches. The resulting MMP inhibitors may serve
as therapeutic leads, as their high specificities will overcome key shortcomings of previous therapeutic
candidates. Precise enzyme disruption in the tumor microenvironment will also lead to a better understanding
of tumor biology at both molecular...

## Key facts

- **NIH application ID:** 9924473
- **Project number:** 5R21CA214239-03
- **Recipient organization:** TUFTS UNIVERSITY MEDFORD
- **Principal Investigator:** James Allen Van Deventer
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $188,150
- **Award type:** 5
- **Project period:** 2018-05-02 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9924473

## Citation

> US National Institutes of Health, RePORTER application 9924473, Discovering hybrid inhibitors for tumor microenvironment disruption (5R21CA214239-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9924473. Licensed CC0.

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