# 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 · $1,007,034

## Abstract

PROJECT SUMMARY
Kennedy’s disease, also known as spinobulbar muscular atrophy (SBMA), is a progressive
neurodegenerative disease caused by genetic polyglutamine expansion 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. The AR pathway is a very
important area being studied in SBMA. 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.
This 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 has provided strong in vivo data that support the submission of this Phase 2
application to continue the preclinical development of ONCT-505 a potential SBMA therapy.
Our objective is to generate certain data for ONCT-505 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:** 10809680
- **Project number:** 5R44NS130806-02
- **Recipient organization:** ONCTERNAL THERAPEUTICS, INC.
- **Principal Investigator:** Rajesh Krishnan
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,007,034
- **Award type:** 5
- **Project period:** 2023-03-15 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10809680

## Citation

> US National Institutes of Health, RePORTER application 10809680, Preclinical development of ONCT-505, an Androgen Receptor Antagonist and Degrader, as new potential therapeutic for Kennedy's Disease (5R44NS130806-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10809680. Licensed CC0.

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