# Project 2: Developing an N-terminal inhibitor of the androgen receptor

> **NIH NIH P50** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $271,789

## Abstract

Project Summary/Abstract
 The overarching goal of this project is to bring a lead compound that targets the androgen receptor
(AR) N-terminal domain to early phase clinical trials with the long-term goal of bringing a drug to regulatory
approval that prolongs life expectancy and improves the quality of life of patients with the metastatic castration
resistant prostate cancer (mCRPC), the stage and state of prostate cancer that accounts for virtually all
prostate cancer-specific mortality. Thus, the key focus of this project is drug discovery and development.
 Several years of preclinical studies and subsequent proof-of-principle clinic trials established a
pathophysiologic role for the AR in the emergence of CRPC. Unfortunately, primary or secondary resistance to
all currently available drugs emerges in all patients. Thus, there is an unmet clinical need to develop effective
therapies that can be applied as single agents in the post-abiraterone/post-enzalutamide setting and potentially
in combination with current secondary generation AR inhibitory agents to improve the quality and quantity of
life of mCRPC patients.
 Importantly, the C-terminal ligand binding domain (LBD) of the AR represents the direct or
indirect molecular target of all hormonally acting agents in clinical use. Other major domains of the AR,
including the centrally located DNA binding domain (DBD) and N-terminal transactivation domain (TAD), have
yet to be directly targeted and exploited for therapeutic benefit. Given that the AR principally functions as a
transcription factor and its genotropic effects are required for the development of castration
resistance, we hypothesized that approaches to inhibit AR transcriptional activity by interfering with
the TAD will suppress the growth of AR-dependent CRPC cells. In pursuit of this hypothesis, the PIs have
collaborated for the last several years to identify a series (the “JN” series) of potent AR inhibitors with the
following characteristics: 1) AR TAD as the molecular target, 2) direct, selective, high affinity and covalent
binding to the AR, 3) drug-induced rapid degradation of the full-length AR (ARFL) and constitutively active AR
splice variants that lack a functional LBD (ARSVs), 4) selective cytoreductive effects on AR expressing prostate
cancer cell lines, including AR∆LBD expressing cell lines, 5) growth inhibition of CRPC xenografts, and 6)
inhibition of AR-driven gene expression. In the advancement of the pre-clinical and clinical development
of JN series compounds, we propose to elucidate the detailed mechanism of action of the JN series
compounds and identify a lead compound through further structure activity relationship analysis that
will be pre-clinically validated and tested in IND-enabling studies. In year 5 of the award, we will initiate
a first-in-human phase 1 study of our lead compound.

## Key facts

- **NIH application ID:** 10000845
- **Project number:** 5P50CA092131-17
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** MATTHEW B RETTIG
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $271,789
- **Award type:** 5
- **Project period:** 2002-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000845

## Citation

> US National Institutes of Health, RePORTER application 10000845, Project 2: Developing an N-terminal inhibitor of the androgen receptor (5P50CA092131-17). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10000845. Licensed CC0.

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