# Novel therapeutics dual targeting intracrine androgen synthesis and AR for advanced prostate cancer

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2024 · $507,346

## Abstract

ABSTRACT
Continued expression of androgen receptor (AR) and its variants, such as AR-V7, despite AR targeted therapy
contributes to treatment resistance and cancer progression in advanced CRPC patients. This highlights the
need for new strategies to block continued AR signaling. Aldo-keto reductase family 1 member C3 (AKR1C3)
is one of the most important genes involved in androgen synthesis and metabolism. Activity of this enzyme
cannot be inhibited by abiraterone. Both AR/AR-V7 and AKR1C3 play key roles in cancer progression and
driving resistance to current therapies. Therefore, inhibition of both AR/AR-V7 and AKR1C3 would be an ideal
strategy for treating advanced prostate cancer (PCa). We have designed a novel strategy to simultaneously
target the AR/AR-V7 and AKR1C3 pathways. We designed and synthesized a library of novel dual
AKR1C3/AR/AR-variant inhibitors, called LX, according to structure-based computer modeling. Of the LX
compounds, LX-1 had the greatest effect at reducing cell number, AR/AR variant expression, and AKR1C3
activity. RNA-seq analysis demonstrated a robust reduction in expression of AR and AR-V7 signaling genes
by the selected LX. LX-1 inhibited conversion of the testosterone precursor androstenedione into testosterone
in tumor cells which express high levels of AKR1C3 in a dose-dependent manner ex vivo. Furthermore,
treatment with LX-1 reduced tumor growth in VCaP and LuCaP35CR PDX xenografts in vivo and decreased
intratumoral testosterone. Based on these findings, the overall hypothesis is that concurrent inhibition of
AR/AR variants and AKR1C3 using novel LX dual inhibitor suppresses CRPC tumor growth, overcomes
resistance and improves treatment response to enzalutamide/abiraterone. This project is to further
characterize LX by understanding its mechanism of action (MOA), determining its efficacy, pharmacokinetics
and toxicity, and to determine their effects on the sensitivity to anti-androgen therapy with the goal to translate
to future clinical development to treat advanced PCa. We hope that completion of the proposed studies will
lead to the development of a new class of therapeutic agents that target both intracrine androgen synthesis
and the AR signaling.

## Key facts

- **NIH application ID:** 10795841
- **Project number:** 5R01CA271327-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Allen C. Gao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $507,346
- **Award type:** 5
- **Project period:** 2022-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10795841

## Citation

> US National Institutes of Health, RePORTER application 10795841, Novel therapeutics dual targeting intracrine androgen synthesis and AR for advanced prostate cancer (5R01CA271327-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10795841. Licensed CC0.

---

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