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

项目摘要 肯尼迪病也被称为脊髓延髓肌萎缩症（SBMA）是一种进行性 由雄激素受体的遗传性多聚谷氨酰胺扩增引起的神经变性疾病 （AR）。最近的研究表明，突变的AR蛋白错误折叠，聚集， 与其他蛋白质发生异常相互作用，导致神经元依赖性下运动神经元 变性和骨骼肌萎缩。目前，没有治疗方法可以阻止 或减缓SBMA的进展，因此，存在严重的未满足的医疗需求，以发现 新的治疗剂。AR通路是目前正在研究的一个非常重要的领域， SBMA。治疗SBMA的实验研究集中在AR与BMA之间的相互作用。 睾丸激素在动物模型中，通过阉割去除睾酮似乎是 保护并潜在地恢复一些失去的功能。SBMA患者来源的AR基因敲除 分化成神经元的干细胞逆转了突变体AR的神经毒性作用。这导致 使用抗雄激素治疗SBMA。 我们的目的是使用临床前模型评估新型选择性AR降解剂（SARD）， SBMA的治疗。设计、合成、表征和构效关系 对大约350种AR靶向小分子的研究导致选择GTx-534和 GTx-505作为我们的主要SARD化合物。SARD已经被广泛研究， 前列腺癌（PCa）模型。重要的是，SARD，不像任何其他分子靶向 AR，结合N-末端结构域（NTD）区域中的AR激活功能-1（AF-1）结构域 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）和药物样性质。的 分子在先导毒理学和药理学研究中没有显示出明显的毒性， 与其他蛋白质的交叉反应。这些特性使GTx-534和GTx-505适合于 在SBMA中进行进一步评估。 这项1期SBIR项目将阐明SARD逆转或 减轻体外和体内AR介导的病理生理过程。这些研究将 提供推进项目进入第2阶段SBIR赠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）。我们已经建立了一个 在激素受体和肌肉骨骼方面拥有丰富经验的优秀团队 研究（Taylor和Narayanan博士）、AR药物化学（米勒博士）和药物发现 和发展（考夫曼博士和Oncternal管理）。

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).