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 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 and evaluate their mechanism of action. Design, synthesis,
characterization, and structure-activity relationship studies of approximately 60 AR-targeting
small molecules provided necessary information to advance to the next stage of structure activity
relationship (SAR) optimization. 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 further optimization. The molecules
also exhibited excellent efficacy in vivo SBMA model.
In this application, we will perform SAR studies to identify and optimize a molecule that is effective
against SBMA in vitro (aim-1) and in vivo (aim 2) models at much lower concentrations than the
1st generation molecules. We will also perform studies to elucidate the mechanism of action of
SARDs and AR (aim 3) in SBMA. We have put together an outstanding team that has extensive
experience in hormone receptor and musculoskeletal research (Dr. Narayanan), AR medicinal
chemistry (Dr. Miller), stem cell biology (Dr. Johnson), animal neurobehavior (Dr. Mulligan), and
pharmacokinetics (Dr. Tan).
