Kennedy's disease also known as spinobulbar muscular atrophy (SBMA) is a progressiveneurodegenerative disease caused by genetic polyglutamine expansion of the androgen receptor(AR). Recent research has shown that the mutant AR protein misfolds, aggregates, andabnormally interacts with other proteins, leading to hormone-dependent lower motor neurondegeneration and skeletal muscle atrophy. Currently, there are no treatments available to stopor slow the progression of the SBMA, therefore, there is dire unmet medical need to discovernovel therapeutic agents. The AR pathway is currently a very important area being studied inSBMA. Experimental studies for the treatment of SBMA have focused on interaction of the ARwith testosterone. Removal of testosterone in animal models through castration appears to beprotective and potentially restores some lost function. Knockout of AR in SBMA patient-derivedstem cells differentiated into neurons reverse the neurotoxic effects of the mutant AR. This led tothe use of antiandrogenic therapies for the SBMA treatment.Our objective is to evaluate novel selective AR degraders (SARDs) using preclinical models forthe treatment of SBMA. Design, synthesis, characterization, and structure-activity relationshipstudies of approximately 350 AR-targeting small molecules led to the selection of GTx-534 andGTx-505 as our lead SARD compounds. The SARDs have been extensively studied in advancedprostate cancer (PCa) models. Importantly, the SARDs, unlike any other molecule targeting theAR, bind to the AR activation function-1 (AF-1) domain in the N-terminus domain (NTD) regionand degrade the AR via the ubiquitin/proteasome pathway. The SARDs are orally bioavailablewith pharmacokinetic (PK) and drug-like properties suitable for clinical development. Themolecules did not show overt toxicity in pilot toxicology and pharmacology studies and also lackcross-reactivity with other proteins. These properties make GTx-534 and GTx-505 suitable forfurther evaluation in SBMA.This Phase 1 SBIR project will elucidate the therapeutic potential of the SARDs to reverse ormitigate the AR-mediated pathophysiological processes in vitro and in vivo. These studies willprovide preliminary data and rationale required to advance the project to a Phase 2 SBIR grantapplication (or directly to a corporate drug development program). We have put together anoutstanding team that has extensive experience in hormone receptor and musculoskeletalresearch (Drs. Taylor and Narayanan), AR medicinal chemistry (Dr. Miller), and drug discoveryand development (Dr. Kaufmann and Oncternal management). PROJECT NARRATIVE
Kennedy's disease is a progressive neurodegenerative disease caused by an abnormal androgen
receptor protein. There is currently no effective treatment available to slow, stop or reverse the
disease. This project will study our SARD molecules that can destroy the androgen receptor
protein as potential therapeutics for Kennedy's disease. Animals ; Castration ; Surgical Castration ; Cells ; Cell Body ; Pharmaceutical Chemistry ; Medicinal Chemistry ; Pharmaceutic Chemistry ; Disease ; Disorder ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Exhibits ; Goals ; Hormone Receptor ; Hormones ; Endocrine Gland Secretion ; Therapeutic Hormone ; In Vitro ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Mus ; Mice ; Mice Mammals ; Murine ; Neurons ; Nerve Cells ; Nerve Unit ; Neural Cell ; Neurocyte ; neuronal ; Patients ; Drug Kinetics ; Pharmacokinetics ; Program Development ; Proteins ; Androgen Receptor ; Research ; Structure-Activity Relationship ; chemical structure function ; structure function relationship ; Testing ; Testosterone ; Therapeutic Testosterone ; Trans-Testosterone ; Ubiquitin ; APF-1 ; ATP-Dependent Proteolysis Factor 1 ; HMG-20 ; High Mobility Protein 20 ; PC12 Cells ; PC-12 ; Pheochromocytoma Cell Line ; pheochromocytoma 12 cell line ; Mediating ; Area ; Phase ; Medical ; multicatalytic endopeptidase complex ; 20S Catalytic Proteasome ; 20S Core Proteasome ; 20S Proteasome ; 20S Proteosome ; Macropain ; Macroxyproteinase ; Multicatalytic Proteinase ; Prosome ; Proteasome ; Proteasome Endopeptidase Complex ; Proteosome ; Evaluation ; Measurement ; Therapeutic ; Therapeutic Agents ; Genetic ; Poly Q ; polyQ ; polyglutamine ; Bulbospinal Neuronopathy ; Kennedy's Disease ; X-Linked Bulbo-Spinal Atrophy ; Kennedy Syndrome ; Oral ; Musculoskeletal ; Degenerative Neurologic Diseases ; Degenerative Neurologic Disorders ; Nervous System Degenerative Diseases ; Neural Degenerative Diseases ; Neural degenerative Disorders ; Neurodegenerative Diseases ; Neurologic Degenerative Conditions ; degenerative diseases of motor and sensory neurons ; degenerative neurological diseases ; neurodegenerative illness ; Neurodegenerative Disorders ; experience ; mutant ; Receptor Protein ; receptor ; receptor bound ; receptor binding ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; Toxicities ; Toxic effect ; Pharmacology and Toxicology ; novel ; Abscission ; Extirpation ; Removal ; Surgical Removal ; resection ; Excision ; Spinobulbar Atrophy ; Spinobulbar Muscular Atrophy ; Modeling ; Property ; cross reactivity ; drug development ; drug discovery ; Bioavailable ; small molecule ; Symptoms ; Data ; Grant Proposals ; Applications Grants ; Preclinical Models ; Pre-Clinical Model ; Receptor Activation ; in vitro Model ; in vivo ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Knock-out ; Knockout ; Process ; Pathway interactions ; pathway ; pre-clinical ; preclinical ; stem cell differentiation ; neuromuscular ; design ; designing ; motor neuron degeneration ; spinal and bulbar muscular atrophy ; Impairment ; Cell model ; Cellular model ; neurotoxic ; neurotoxicity ; neuron toxicity ; neuronal toxicity ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; induced pluripotent stem cell ; iPS ; iPSC ; iPSCs ; FDA approved ; effective therapy ; effective treatment ; skeletal muscle wasting ; skeletal muscle atrophy ; skeletal muscle breakdown ; skeletal muscle loss ; skeletal muscle protein loss ; prostate cancer model ; prostate tumor model ; Pharmacology Study ; Pharmacological Study ; experimental study ; experiment ; experimental research ; clinical development ; advanced prostate cancer ;
