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

选择性雄激素受体降解剂（SARD）作为脊髓和延髓肌萎缩症（SBMA）的新疗法

基本信息

批准号：
10259452
负责人：
Gunnar Joerg Floris Kaufmann
金额：
$ 29.77万
依托单位：
ONCTERNAL THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10259452
关键词：
Androgen Receptor Animal Model Animals Applications Grants Area Bioavailable Castration Cell model Cells Data Disease Drug Kinetics Evaluation Excision Exhibits FDA approved Genetic Goals Hormone Receptor Hormones Impairment In Vitro Kennedy Syndrome Knock-out Lead Measurement Mediating Medical Modeling Mus Musculoskeletal Neurodegenerative Disorders Neurons Oral PC12 Cells Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Study Pharmacology and Toxicology Phase Pre-Clinical Model Process Program Development Property Proteins Receptor Activation Research Small Business Innovation Research Grant Spinobulbar Muscular Atrophy Structure-Activity Relationship Symptoms Testing Testosterone Therapeutic Therapeutic Agents Toxic effect Ubiquitin advanced prostate cancer clinical development cross reactivity design drug development drug discovery effective therapy experience experimental study in vitro Model in vivo induced pluripotent stem cell motor neuron degeneration multicatalytic endopeptidase complex mutant neuromuscular neurotoxic neurotoxicity novel novel therapeutics polyglutamine pre-clinical prostate cancer model receptor receptor binding skeletal muscle wasting small molecule spinal and bulbar muscular atrophy stem cell differentiation

项目摘要

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).

项目概要肯尼迪病也称为脊髓延髓肌萎缩症 (SBMA)，是一种进行性的疾病雄激素受体遗传性聚谷氨酰胺扩张引起的神经退行性疾病 (AR) 最近的研究表明，突变的 AR 蛋白会发生错误折叠、聚集和聚集。与其他蛋白质异常相互作用，导致激素依赖性下运动神经元目前，没有任何治疗方法可以阻止退化和骨骼肌萎缩。或减缓 SBMA 的进展，因此，迫切需要发现未满足的医学需求 AR途径是目前正在研究的一个非常重要的领域。 SBMA 治疗的实验研究集中在 AR 的相互作用上。通过阉割去除动物模型中的睾酮似乎是 SBMA 患者来源的 AR 敲除具有保护性并可能恢复一些丧失的功能。干细胞分化成神经元逆转了突变 AR 的神经毒性作用。使用抗雄激素疗法进行 SBMA 治疗。我们的目标是使用临床前模型评估新型选择性 AR 降解剂 (SARD) SBMA 的设计、合成、表征和构效关系。对大约 350 个 AR 靶向小分子的研究导致选择了 GTx-534 和 GTx-505 作为我们的主要 SARD 化合物，已对 SARD 进行了广泛的高级研究。重要的是，SARD 与任何其他靶向前列腺癌 (PCa) 的分子不同。 AR，与 N 末端结构域 (NTD) 区域的 AR 激活功能 1 (AF-1) 结构域结合并通过泛素/蛋白酶体途径降解 AR。 SARD 具有口服生物利用度。具有适合临床开发的药代动力学（PK）和类药特性。分子在初步毒理学和药理学研究中没有表现出明显的毒性，也缺乏这些特性使 GTx-534 和 GTx-505 适合用于 SBMA 进一步评估。该第一阶段 SBIR 项目将阐明 SARD 逆转或逆转的治疗潜力这些研究将在体外和体内减轻 AR 介导的病理生理过程。提供将项目推进第 2 阶段 SBIR 拨款所需的初步数据和理由申请（或直接申请公司药物开发计划）。优秀的团队，在激素受体和肌肉骨骼领域拥有丰富的经验研究（Taylor 博士和 Narayanan 博士）、AR 药物化学（Miller 博士）和药物发现和发展（Kaufmann 博士和 Oncternal 管理层）。