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

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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).