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).

项目摘要肯尼迪氏病也称为脊柱肌萎缩症（SBMA）是一种进步由雄激素受体的遗传聚谷氨酰胺膨胀引起的神经退行性疾病（ar）。最近的研究表明，突变的AR蛋白不折叠，聚集体和交替与其他蛋白质相互作用，从而导致依赖马的下运动神经元变性和骨骼肌萎缩。目前，没有可用的治疗方法可以停止或减慢SBMA的进展，因此，有可怕的医疗需要发现新型热剂。目前，AR途径是一个非常重要的领域 SBMA。用于治疗SBMA的实验研究集中于AR的相互作用与睾丸激素。通过casttration去除动物模型中的睾丸激素似乎是保护性并有可能恢复一些损失的功能。 SBMA患者衍生的AR敲除分化为神经元的干细胞逆转了突变AR的神经毒性作用。这导致了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颖的选择性AR降解器（SARD） SBMA的处理。设计，合成，表征和结构活性关系大约350个靶向AR的小分子的研究导致选择GTX-534和 GTX-505作为我们的铅sard化合物。撒特在高级方面已广泛研究前列腺癌（PCA）模型。重要的是，与其他针对的其他分子不同 AR，与N末端域（NTD）区域中的AR激活函数-1（AF-1）结构域结合并通过泛素/蛋白酶体途径降解AR。种子是口服生物利用的具有适用于临床发育的药代动力学（PK）和类似药物的特性。这分子在试验毒理学和药理学研究中没有表现出明显的毒性，也缺乏与其他蛋白质的交叉反应性。这些特性使GTX-534和GTX-505适合 SBMA进一步评估。该第1阶段SBIR项目将阐明sards逆转或在体外和体内减轻AR介导的病理生理过程。这些研究会提供将项目推向第二阶段SBIR赠款所需的初步数据和基本原理应用（或直接用于公司药物开发计划）。我们把一个杰出团队在同性接收器和肌肉骨骼方面拥有丰富的经验研究（Taylor和Narayanan博士），AR药物化学（Miller博士）和药物发现和开发（Kaufmann博士和Oncternal Management）。