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

项目摘要 肯尼迪病，也称为脊髓延髓肌萎缩症（SBMA），是一种进行性 由N-末端结构域的遗传性多聚谷氨酰胺扩增引起的神经变性疾病 (NTD)雄激素受体（AR）。最近的研究表明，突变的AR蛋白 错误折叠，聚集，并与其他蛋白质异常相互作用，导致雄激素- 依赖性下运动神经元变性和骨骼肌萎缩。目前有 没有可用的治疗来减缓，停止甚至逆转SBMA的进展，因此， 发现新的治疗剂是高度未满足的医学需求。AR途径是一个非常 在SBMA研究的重要领域。治疗SBMA的实验研究 研究AR与睾丸激素的相互作用去势去除动物体内睾酮 模型似乎是保护和恢复一些失去的功能。SBMA患者中的AR敲除- 分化成神经元的衍生干细胞逆转突变体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1阶段SBIR 授予评估我们的NTD结合选择性AR拮抗剂和降解剂（DAARI）在临床前 SBMA模型提供了强有力的体内数据，支持本II期研究的提交。 申请继续ONCT-505的临床前开发，这是一种潜在的SBMA疗法。 我们的目标是为ONCT-505生成最终支持提交的某些数据 研究性新药（IND）申请。ONCT-505已经在各种研究中进行了研究。 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，与靶向AR的任何其他分子不同，ONCT-505结合AR活化 功能-1（AF-1）结构域，并导致信号转导拮抗作用，最终导致AR蛋白 通过泛素/蛋白酶体途径降解。ONCT-505具有口服生物利用度， 药代动力学（PK）和药物样特性适合药物开发，并证明 SBMA临床前模型的疗效优于手术去势。这个分子并没有表现出 在初步毒理学研究中，明显毒性高达ED50（50%观察到疗效的有效剂量）的200倍 研究，也缺乏与其他蛋白质的交叉反应性。这些特性使ONCT-505成为 作为潜在小分子治疗剂进一步评价的理想候选物， 在SBMA。 成功完成概述的研究将产生临床候选药物， 已证明临床前疗效、有据可查的安全性特征以及可扩展的GMP兼容性 制造过程

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.