Preclinical development of ONCT-505, an Androgen Receptor Antagonist and Degrader, as new potential therapeutic for Kennedy's Disease

ONCT-505（一种雄激素受体拮抗剂和降解剂）的临床前开发，作为肯尼迪病的新潜在治疗方法

• 批准号: 10603636
• 负责人: Rajesh Krishnan
• 金额: $ 75.37万
• 依托单位: ONCTERNAL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10603636
• 关键词: Androgen Receptor; Animal Model; Applications Grants; Area; Award; Binding; Binding Proteins; Biological Assay; Biological Availability; Caco-2 Cells; Castration; Chemistry; Clinical; Data; Development; Development Plans; Disease; Dose; Drug Kinetics; Engineering; Evaluation; Follow-Up Studies; Formulation; Funding; Genetic; Grant; Hormone Receptor; In Vitro; Industry; Investigational New Drug Application; Kennedy Syndrome; Knock-out; Manuals; Medical; Metabolic; Mitochondria; Musculoskeletal; Mutagenicity Tests; N-terminal; Neurodegenerative Disorders; Neurons; Oral; Pathologic; Pathway interactions; Patients; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phenotype; Plasma Proteins; Pre-Clinical Model; Process; Productivity; Property; Proteins; Receptor Activation; Receptor Aggregation; Records; Regulatory Affairs; Research; Rodent; Safety; Series; Signal Transduction; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Spinobulbar Muscular Atrophy; Testosterone; Therapeutic; Therapeutic Agents; Toxic effect; Toxicokinetics; Toxicology; Transgenic Mice; Transgenic Model; Ubiquitin; United States Food and Drug Administration; advanced prostate cancer; androgen sensitive; androgenic; antagonist; cross reactivity; drug candidate; drug development; effective therapy; efficacy evaluation; efficacy study; experience; experimental study; in vivo; manufacture; manufacturing process; medication safety; motor neuron degeneration; multicatalytic endopeptidase complex; mutant; neurotoxic; novel therapeutics; pharmacologic; phase I trial; polyglutamine; pre-Investigational New Drug meeting; pre-clinical; preclinical development; preclinical efficacy; process optimization; protein degradation; receptor; safety study; scale up; skeletal muscle wasting; small molecule therapeutics; stem cell differentiation

PROJECT SUMMARY Kennedy’s disease, also known as spinobulbar muscular atrophy (SBMA), is a progressive neurodegenerative disease caused by genetic polyglutamine expansion in the N-terminal domain (NTD) of the androgen receptor (AR). Recent research has shown that the mutant AR protein misfolds, aggregates, and abnormally interacts with other proteins, leading to androgen- dependent lower motor neuron degeneration and skeletal muscle atrophy. Currently, there are no treatments available to slow, stop or even reverse the progression of SBMA, therefore, the unmet medical need is high to discover novel therapeutic agents. The AR pathway is a very important area being studied in SBMA. Experimental studies for the treatment of SBMA have focused on interaction of the AR with testosterone. Removing testosterone via castration in animal models appears to be protective and restores some lost function. AR knockout in SBMA patient- derived stem cells differentiated into neurons reverses the neurotoxic effects of the mutant AR. This led to the use of anti-androgenic therapies for SBMA treatment. Our awarded Phase 1 SBIR grant to evaluate our NTD-binding selective AR antagonists and degraders (DAARIs) in preclinical models of SBMA has provided strong in vivo data that support the submission of this Phase 2 application to continue the preclinical development of ONCT-505 a potential SBMA therapy. Our objective is to generate certain data for ONCT-505 that will ultimately support the submission of an investigational new drug (IND)-application. ONCT-505 has been studied in various preclinical models of AR-dependent diseases, including SBMA and advanced prostate cancer. Importantly, ONCT-505, unlike any other molecule targeting the AR, binds to the AR activation function-1 (AF-1) domain in the NTD and leads to signaling antagonism and ultimately AR protein degradation via ubiquitin/proteasome pathway. ONCT-505 is orally bioavailable with pharmacokinetic (PK) and drug-like properties suitable for drug development and demonstrated efficacy in SBMA preclinical models better than surgical castration. The molecule did not show overt toxicity up to 200 times the ED50 (effective dose of 50% observed efficacy) in pilot toxicology studies and also lacks cross-reactivity with other proteins. These properties make ONCT-505 an ideal candidate for further evaluation as potential small molecule therapeutic for patients suffering from SBMA. Successful completion of the outlined studies will result in a clinical drug candidate with demonstrated preclinical efficacy, well-documented safety profile, and scalable GMP-compatible manufacturing process.

项目摘要 肯尼迪氏病，也称为脊柱肌肉萎缩（SBMA），是一种进步 由N末端结构域中遗传聚谷氨酰胺扩张引起的神经退行性疾病 雄激素受体（AR）的（NTD）。最近的研究表明，突变AR蛋白 错误折叠，聚集体和绝对性与其他蛋白质相互作用，导致雄激素 依赖性运动神经元变性和骨骼肌萎缩。目前，有 因此，没有可用的治疗方法可以放慢，停止甚至扭转SBMA的进展，因此， 未满足的医疗需求很高，可以发现新型的治疗剂。 AR路径非常 在SBMA中研究的重要区域。用于治疗SBMA的实验研究 专注于AR与睾丸激素的相互作用。通过cast割动物去除睾丸激素 模型似乎受到保护并恢复一些丢失的功能。 SBMA患者的AR敲除 - 分化为神经元的衍生干细胞会逆转突变AR的神经毒性作用。 这导致使用抗雄激素疗法进行SBMA治疗。我们授予的第一阶段SBIR 授予临床前评估我们的NTD结合选择性AR拮抗剂和降解者（Daaris） SBMA的模型提供了强大的体内数据，以支持此阶段2的提交 继续进行ONCT-505的临床前开发A潜在的SBMA治疗。 我们的目标是生成ONCT-505的某些数据，该数据最终将支持提交 研究性新药（IND） - 申请。 ONCT-505已经研究了各种 AR依赖性疾病的临床前模型，包括SBMA和晚期前列腺癌。 重要的是，与AR的任何其他分子不同，ONCT-505与AR激活结合 NTD中的功能1（AF-1）结构域，并导致信号拮抗作用，并最终导致AR蛋白 通过泛素/蛋白酶体途径降解。 onct-505是口服生物利用的 适用于药物开发的药代动力学（PK）和类似药物的特性 SBMA临床前模型的功效比手术cast割更好。分子没有显示 在试验毒理学中，ED50的明显毒性高达200倍（有效剂量为50％的有效剂量） 研究，也缺乏与其他蛋白质的交叉反应性。这些属性使ONCT-505成为 作为患者的潜在小分子疗法，进行进一步评估的理想候选者 来自SBMA。 成功完成概述研究将导致临床药物候选者 展示了临床前效率，有据可查的安全性和可扩展的GMP兼容 制造过程。