# Development of Next Generation Galeterone Analogs for Prostate Cancer Therapy

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $448,418

## Abstract

The overall long-term goal of this project is the development of safer, more effective drugs for the treatment of
prostate cancer (PC). Androgen receptor [AR, including its splice variants] and Mnk activated eIF4E signaling
promote the development, progression, and metastasis of PC, in addition to induction of resistance to a variety
of drugs. We recently developed clinical candidate galeterone (gal) which disrupts AR signaling via multiple
mechanisms of action (1). Gal progressed into pivotal Phase III clinical trial in patients with metastatic castration-
resistant PC (mCRPC) whose tumor cells express splice variant AR-V7 (ARMOR3-SV). However, the recent
termination of this trial (due to trial design flaws) and the required 2550 mg/day high therapeutic dose of gal
underscores the need to further systematic refinements to enable development of the next generation gal
analogs (NGGAs) with enhanced efficacies and high therapeutic indices at low dose-administration expected
to result in safer, more effective treatments across all stages/forms of PC. In the course of studies to develop
NGGAs to modulate AR signaling in PC models (2), we discovered that gal and its new more efficacious analogs
(VNPP414 and VNPP433-3β) also effectively target oncogenic eukaryotic protein translation, via modulation of
Mnk-eIF4E axis (3). These compounds also suppress oncogenic peIF4E via degradation of Mnk1 and 2, and as
such, are also referred to as Mnk degrading agents (MNKDAs). The objective of this application is to determine
the therapeutic potential of lead NGGA, VNPP433-3β that simultaneously target both AR/AR-V7 and Mnk/eIF4E
for the treatment of all forms of PC, including metastatic disease. In preliminary studies, gal and our new lead
NGGAs degraded AR/AR-Vs, Mnk1/2, inhibited PSA synthesis and secretion, blocked cell cycle progression and
growth of human PC cells in culture, induced apoptosis, and inhibited cell migration, invasion, and putative stem
cell markers and reversed the expression of epithelial-to-mesenchymal transition (EMT), suggesting a direct
inhibitory effect on the neoplastic process. In addition, the new NGGAs (alone and in combination) also inhibited
the growth of gal-, enzalutamide-, docetaxel-, and mitoxantrone-resistant human PC cell lines. Importantly, initial
in vivo testing showed that VNPP433-3β (at 7.53-fold lower equimolar dose than gal) markedly suppressed (84%
vs. gal, 47%; p < 0.01) the growth of castration-resistant 22Rv1 xenograft tumors, with no apparent host toxicity.
Based on these strong preliminary data, we hypothesize that our novel NGGAs possess superb multiple
desirable anti-PC activities as single agents and can synergize (with increased anti-PC activity) when combined
with FDA approved PC drugs. In this proposal, we will conduct, through 3 comprehensive and hypothesis-driven
specific aims, basic/translational pre-clinical research, focusing on lead VNPP433-3β, with the goal to
understand the full mechanisms of actio...

## Key facts

- **NIH application ID:** 10104455
- **Project number:** 5R01CA224696-04
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** VINCENT Collins Ofuka NJAR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $448,418
- **Award type:** 5
- **Project period:** 2018-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10104455

## Citation

> US National Institutes of Health, RePORTER application 10104455, Development of Next Generation Galeterone Analogs for Prostate Cancer Therapy (5R01CA224696-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10104455. Licensed CC0.

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