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

项目总结 肯尼迪病又称脊髓延髓肌萎缩症(SBMA)，是一种进行性 雄激素受体遗传性多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蛋白错误折叠、聚集和 异常地与其他蛋白质相互作用，导致激素依赖的下运动神经元 变性和骨骼肌萎缩。目前，还没有可以停止的治疗方法。 或减缓SBMA的进展，因此，有迫切的未得到满足的医疗需求需要发现 新型治疗剂。AR通路是目前正在研究的一个非常重要的领域 SBMA。治疗SBMA的实验研究主要集中在AR的相互作用上 含有睾丸素。在动物模型中通过去势去除睾丸激素似乎是 具有保护性，有可能恢复一些丧失的功能。SBMA患者来源的AR基因敲除 分化为神经元的干细胞逆转了突变AR的神经毒性效应。这导致了 抗雄激素治疗在SBMA治疗中的应用。 我们的目标是使用临床前模型评估新型选择性AR降解物(SARD) SBMA的治疗。设计、合成、表征及构效关系 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SARD先导化合物。SARD已在高级阶段进行了广泛的研究 前列腺癌(PCA)模型。重要的是，SARD不同于任何其他针对 AR，与N-末端结构域(NTD)中的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是口服生物利用型的 具有适合临床开发的药代动力学(PK)和类药物特性。这个 在初步的毒理学和药理学研究中，分子没有显示出明显的毒性，也缺乏 与其他蛋白质的交叉反应。这些特性使GTx-534和GTx-505适用于 在SBMA中进行进一步评估。 该第一阶段SBIR项目将阐明SARD的治疗潜力，以逆转或 减轻AR介导的体内外病理生理过程。这些研究将 提供将项目推进到第二阶段SBIR拨款所需的初步数据和理由 申请(或直接向公司药物开发计划申请)。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(泰勒博士和纳拉亚南博士)、AR药物化学(米勒博士)和药物发现 和发展(考夫曼博士和永恒管理)。

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).