# Targeting androgen receptor nuclear localization in prostate cancer

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $374,450

## Abstract

Project Summary
Title: Targeting androgen receptor nuclear localization in prostate cancer
Prostate cancer (PCa) is the most frequently diagnosed cancer and second leading cause of cancer death in
American men. More effective therapies for PCa are urgently needed. The androgen receptor (AR) is a key
therapeutic target for PCa. AR appears to be overexpressed, stabilized, and nuclear-localized in castration-
resistant PCa (CRPC). AR nuclear localization is necessary for its function as a transcription factor. We have
developed a high-throughput screen and identified two closely related pyrroloimidazoles, CPPI and EPPI,
which can inhibit AR nuclear localization in CRPC. These small molecules inhibited all tested AR-positive
prostate cancer cells, including enzalutamide-resistant CRPC. Further studies suggested that these small
molecules can directly bind to AR and enhance AR ubiquitination and degradation in the nucleus, acting as
nuclear AR degraders (NARDs). Since CRPC is associated with increased AR level and stability, inhibition or
even partial inhibition of AR level may slow down the progression to CRPC. Here, we hypothesize that NARD
can inhibit CRPC and prostate cancer progression to castration resistance. Also, NARD may enhance the
efficacy of other AR targeting agents because resistance to AR targeting agents is also associated with
increased AR expression. To explore the therapeutic potential of NARD, 3 specific aims are proposed. Aim 1
will determine the mechanisms by which CPPI inhibits AR nuclear localization in CRPC cells. Aim 2 will
evaluate potential synergies of CPPI with other AR-targeting approaches. Aim 3 will synthesize and
characterize novel analogues of CPPI with the goal to identify new lead NARD compounds with submicromolar
potency and high specificity for AR-positive PCa cells. Success of the proposed project may lead a strategy to
slow down the progression of prostate cancer to castration resistance and to an alternative approach to
PROTAC AR degraders, which are being actively investigated as a therapeutic agent for AR-positive CRPC.
Since the mechanisms of NARD action are different from PROTAC-type AR degraders, NARD may be more
suitable than PROTAC AR degraders in certain patient populations.

## Key facts

- **NIH application ID:** 10335481
- **Project number:** 1R01CA265897-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Zhou Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $374,450
- **Award type:** 1
- **Project period:** 2022-06-10 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10335481

## Citation

> US National Institutes of Health, RePORTER application 10335481, Targeting androgen receptor nuclear localization in prostate cancer (1R01CA265897-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10335481. Licensed CC0.

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