# Chimeric Inhibitors of Androgen Biosynthesis and Signaling

> **NIH NIH F31** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $36,844

## Abstract

PROJECT ABSTRACT
Chimeric Inhibitors of Androgen Biosynthesis and Signaling
Androgens drive the progression of over 80% of prostate cancer tumors. Therefore, treatment strategies often
use surgical or chemical castration to disrupt the signaling of these steroid hormones through the androgen
receptor (AR). Despite the initial efficacy of such therapies, patients inevitably develop resistance leading to
castration-resistant prostate cancer (CRPC), which is sustained by very low androgen levels in the body. Of the
few drugs approved for this advanced and fatal stage of the disease, the prodrug abiraterone acetate is the only
one designed to target cytochrome P450 17A1 (CYP17A1), an enzyme required for androgen production. In
patients, abiraterone (the primary active agent) is converted into the more potent Δ4-abiraterone, which both
inhibits CYP17A1 and antagonizes the AR. Unfortunately, Δ4-abiraterone does not significantly accumulate in
patients. Instead, this metabolite is irreversibly modified by 5α-reductase into an AR agonist, which actually
promotes prostate cancer cell growth (similar to endogenous androgens). In order to address this immediate
medical need, the goal of this proposal is to design analogues of Δ4-abiraterone that avoid unwanted metabolism
by 5α-reductase but still interrupt androgen biosynthesis and signaling at multiple points. To this end, the
immediate objective is to replace the key metabolic liability of Δ4-abiraterone, while maintaining potency and
enhancing selectivity at CYP17A1, one of the primary drug targets. Accordingly, the following aims will be
pursued: (1a) replace the key metabolic liability of Δ4-abiraterone, (1b) improve the selectivity of synthesized
analogues for CYP17A1, and (2) explore 3-pyridyl substituent effects on the polypharmacology of Δ4-abiraterone.
The compounds described in this proposal are also designed to inhibit 5α-reductase and antagonize the AR,
which is expected to lead to greater anti-tumor activity than Δ4-abiraterone itself. In collaboration with researchers
from the University of Michigan-Ann Arbor and the University of North Carolina at Chapel Hill, some of the
polypharmacology of the proposed compounds will be characterized against key drug targets of CRPC (i.e.,
CYP17A1, 5α-reductase, and the AR). If the immediate objective is achieved, this research project would
demonstrate that mimics of the more potent Δ4-abiraterone can be rationally designed, facilitating the
development of more effective treatments for advanced stage prostate cancer.

## Key facts

- **NIH application ID:** 9891847
- **Project number:** 5F31CA239322-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Caleb D. Vogt
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $36,844
- **Award type:** 5
- **Project period:** 2019-02-19 → 2021-02-18

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891847

## Citation

> US National Institutes of Health, RePORTER application 9891847, Chimeric Inhibitors of Androgen Biosynthesis and Signaling (5F31CA239322-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9891847. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*