# Preclinical development of ONCT-505, an Androgen Receptor Antagonist and Degrader, as New Potential Therapeutic for Kennedy's Disease

> **NIH NIH R44** · ONCTERNAL THERAPEUTICS, INC. · 2024 · $50,000

## Abstract

Project Summary:
Kennedy’s disease, also known as spinobulbar muscular atrophy (SBMA), is a progressive
neurodegenerative disease caused by genetic polyglutamine copies in the N-terminal domain
(NTD) of the androgen receptor (AR). Recent research has shown that the mutant AR protein
misfolds, aggregates, and abnormally interacts with other proteins, leading to androgen dependent
lower motor neuron degeneration and skeletal muscle atrophy. Currently, there are no treatments
available to slow, stop or even reverse the progression of SBMA; therefore, the unmet medical need
is high to discover novel therapeutic agents against the disease. Experimental studies for the
treatment of SBMA have focused on interaction of the AR with testosterone. Removing
testosterone via castration in animal models appears to be protective and restores some lost
function. AR knockout in SBMA patient-derived stem cells differentiated into neurons reverses the
neurotoxic effects of the mutant AR.
These findings have led to the use of anti-androgenic therapies for SBMA treatment. Our awarded
Phase 1 SBIR grant to evaluate our NTD-binding selective AR antagonists and degraders (DAARIs) in
preclinical models of SBMA and our Phase 2 SBIR grant have generated strong in vitro and in vivo
data, and preclinical manufacturing development to progress the development of ONCT-505 as a
potential SBMA therapy.
Our objective is to generate specific data for ONCT-505, described below, that will ultimately
support the submission of an investigational new drug (IND)-application. ONCT-505 has been
studied in various preclinical models of AR-dependent diseases, including SBMA and advanced
prostate cancer. Importantly, ONCT-505, unlike any other molecule targeting the AR, binds to the
AR activation function-1 (AF-1) domain in the NTD and leads to signaling antagonism and ultimately
AR protein degradation via ubiquitin/proteasome pathway. ONCT-505 is orally bioavailable with
pharmacokinetic (PK) and drug-like properties suitable for drug development and demonstrated
efficacy in SBMA preclinical models better than surgical castration. The molecule did not show
overt toxicity up to 200 times the ED50 (effective dose of 50% observed efficacy) in pilot toxicology
studies and also lacks cross reactivity with other proteins. These properties make ONCT-505 an
ideal candidate for further evaluation as potential small molecule therapeutic for patients suffering
from SBMA.
Successful completion of the outlined studies will result in a clinical drug candidate with
demonstrated preclinical efficacy, well-documented safety profile, and scalable GMP-compatible
manufacturing process.

## Key facts

- **NIH application ID:** 11107781
- **Project number:** 3R44NS130806-02S1
- **Recipient organization:** ONCTERNAL THERAPEUTICS, INC.
- **Principal Investigator:** Rajesh Krishnan
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $50,000
- **Award type:** 3
- **Project period:** 2023-03-15 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11107781

## Citation

> US National Institutes of Health, RePORTER application 11107781, Preclinical development of ONCT-505, an Androgen Receptor Antagonist and Degrader, as New Potential Therapeutic for Kennedy's Disease (3R44NS130806-02S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11107781. Licensed CC0.

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