# Selective Androgen Receptor Degraders (SARDs) as new therapeutics for spinal and bulbar muscular atrophy (SBMA)

> **NIH NIH R41** · ONCTERNAL THERAPEUTICS, INC. · 2021 · $297,671

## Abstract

PROJECT SUMMARY
Kennedy’s disease also known as spinobulbar muscular atrophy (SBMA) is a progressive
neurodegenerative disease caused by genetic polyglutamine expansion of the androgen receptor
(AR). Recent research has shown that the mutant AR protein misfolds, aggregates, and
abnormally interacts with other proteins, leading to hormone-dependent lower motor neuron
degeneration and skeletal muscle atrophy. Currently, there are no treatments available to stop
or slow the progression of the SBMA, therefore, there is dire unmet medical need to discover
novel therapeutic agents. The AR pathway is currently a very important area being studied in
SBMA. Experimental studies for the treatment of SBMA have focused on interaction of the AR
with testosterone. Removal of testosterone in animal models through castration appears to be
protective and potentially restores some lost function. Knockout of AR in SBMA patient-derived
stem cells differentiated into neurons reverse the neurotoxic effects of the mutant AR. This led to
the use of antiandrogenic therapies for the SBMA treatment.
Our objective is to evaluate novel selective AR degraders (SARDs) using preclinical models for
the treatment of SBMA. Design, synthesis, characterization, and structure-activity relationship
studies of approximately 350 AR-targeting small molecules led to the selection of GTx-534 and
GTx-505 as our lead SARD compounds. The SARDs have been extensively studied in advanced
prostate cancer (PCa) models. Importantly, the SARDs, unlike any other molecule targeting the
AR, bind to the AR activation function-1 (AF-1) domain in the N-terminus domain (NTD) region
and degrade the AR via the ubiquitin/proteasome pathway. The SARDs are orally bioavailable
with pharmacokinetic (PK) and drug-like properties suitable for clinical development. The
molecules did not show overt toxicity in pilot toxicology and pharmacology studies and also lack
cross-reactivity with other proteins. These properties make GTx-534 and GTx-505 suitable for
further evaluation in SBMA.
This Phase 1 SBIR project will elucidate the therapeutic potential of the SARDs to reverse or
mitigate the AR-mediated pathophysiological processes in vitro and in vivo. These studies will
provide preliminary data and rationale required to advance the project to a Phase 2 SBIR grant
application (or directly to a corporate drug development program). We have put together an
outstanding team that has extensive experience in hormone receptor and musculoskeletal
research (Drs. Taylor and Narayanan), AR medicinal chemistry (Dr. Miller), and drug discovery
and development (Dr. Kaufmann and Oncternal management).

## Key facts

- **NIH application ID:** 10259452
- **Project number:** 1R41NS122647-01
- **Recipient organization:** ONCTERNAL THERAPEUTICS, INC.
- **Principal Investigator:** Gunnar Joerg Floris Kaufmann
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $297,671
- **Award type:** 1
- **Project period:** 2021-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10259452

## Citation

> US National Institutes of Health, RePORTER application 10259452, Selective Androgen Receptor Degraders (SARDs) as new therapeutics for spinal and bulbar muscular atrophy (SBMA) (1R41NS122647-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10259452. Licensed CC0.

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