# Peptoid conjugates targeting prostate cancer

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $624,001

## Abstract

PROJECT SUMMARY
We propose an innovative approach to antagonize the androgen receptor (AR) by displaying AR ligands on a
peptoid scaffold. This new family of molecules, called multivalent peptoid conjugates (MPCs), potently stops
the growth of prostate cancer cells resistant to treatment by standard anti-androgen agents such as
enzalutamide. Peptoids are small protein-like chains, but unlike polypeptides, they are protease resistant and
thus exhibit improved pharmacologic stability, favorable solubility, and cell permeability characteristics, making
them an attractive option for drug development. Our published and preliminary studies show that MPCs deter
prostate cancer growth by antagonizing the proliferative response of AR. We propose that MPCs promote a
novel AR conformation that drives a different pattern of AR-mediated gene expression compared to DHT or
enzalutamide resulting in a block to cell proliferation by the gain and loss of AR occupancy at select genomic
sites. We will perform ChIP-seq, RNA-seq, and ChIP-mass spec to identify MPC target genes and the
coregulatory factors controlling their expression compared to enzalutamide and DHT in enzalutamide-resistant
cells.
In addition, MPCs can promote immune cell infiltration in treated xenograft prostate tumors, which could
potentiate a cytotoxic T cell response and enhance the efficacy of immune checkpoint blockade (ICB), allowing
the patient’s immune system to fight tumor growth. The inadequacy of available immune checkpoint blockade
strategies is an obstacle to treating advanced prostate cancer. We will determine whether MPCs can promote
anti-tumor immunity and sensitize tumors to ICB treatment. Therefore, another goal of this proposal will be to
assess whether MPC309 can synergize with ICB antibodies in treating CRPC.
We will also conduct X-ray crystallography studies to establish the mechanism of action of MPC309 with AR.
This will provide insights into the molecular interactions between MCP309 and AR and will be used to guide
the design of more potent and selective MPCs optimized for AR antagonism. Thus, MPCs can stop the growth
of prostate cancer cells that have adapted to treatment by developing drug resistance and have the potential to
lead to the development of novel and effective therapies for patients with advanced prostate cancer.

## Key facts

- **NIH application ID:** 10812127
- **Project number:** 1R01CA276438-01A1
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Michael J. Garabedian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $624,001
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10812127

## Citation

> US National Institutes of Health, RePORTER application 10812127, Peptoid conjugates targeting prostate cancer (1R01CA276438-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10812127. Licensed CC0.

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