Drug Discovery Pipeline Targeting Pathologically Leaky Calcium Release Channels in Age-Related Indications

针对年龄相关适应症中病理性渗漏钙释放通道的药物研发管线

• 批准号: 10157143
• 负责人: RAZVAN LIVIU CORNEA
• 金额: $ 49.94万
• 依托单位: PHOTONIC PHARMA, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10157143
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease model; Animals; Binding; Biological Assay; Brain; Calcium; Calcium Signaling; Calmodulin; Cell physiology; Cells; Chemicals; Chicago; Clinical; Collaborations; Complement; Development; Dose; Endoplasmic Reticulum; Ensure; FKBP1B gene; Family suidae; Fluorescence; Fluorescence Resonance Energy Transfer; Functional disorder; Funding; Future; Grant; Heart; Human; In Situ; Individual; Interruption; Label; Lead; Legal patent; Letters; Libraries; Licensing; Membrane; Monitor; Muscle; Myocardium; Neurons; Organelles; Pathogenesis; Pathologic; Pathology; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Protein Isoforms; Reader; Research; Rest; RyR1; RyR2; RyR3; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Skeletal Muscle; Small Business Innovation Research Grant; Source; Specificity; Structure; Structure-Activity Relationship; System; Systems Analysis; Tacrolimus Binding Proteins; Technology; Therapeutic; Translating; Universities; Validation; Vesicle; Work; age related; age related neurodegeneration; analog; base; commercialization; design; drug discovery; experience; follow-up; high throughput screening; inhibitor/antagonist; interest; novel therapeutic intervention; photonics; prevent; receptor function; response; screening; small molecule; targeted agent; therapeutic target

Project Summary Photonic Pharma LLC (PP) proposes a Phase I SBIR project to launch high-throughput screening (HTS) for discovery of small-molecule allosteric inhibitors of pathologically leaky ryanodine receptor (RyR) calcium (Ca) release channels, to arrest or reverse age-related neurodegeneration, focused on Alzheimer’s disease (AD). In AD, dysregulated intracellular Ca fuels a pathophysiological vicious cycle. RyRs are responsible for triggered Ca release from intracellular storage organelles (sarcoplasmic reticulum – SR; endoplasmic reticulum – ER). The resulting Ca signaling is essential for many cellular processes in muscle and non-muscle cells. Dysregulated RyR function, producing a Ca-leaky state of the resting ER/SR, has been identified as a key contributor to age-related pathologies, particularly AD. In this proposal, we target RyR2, the predominant brain isoform, which has been clearly identified as a target for AD pathogenesis and therapy. We have translated our academic research at UMN toward fluorescence-based HTS structural assays targeting RyR2 (US patent 10,281,476). This FRET assay uses fluorescently labeled RyR2 modulators, calmodulin (CaM) and FKBP12.6 (FKBP), to monitor RyR2-CaM binding. Using small pilot screens, we have demonstrated an inverse correlation between compound effects on our FRET readout and resting RyR2 activity (Ca leak). This established an HTS platform to identify allosteric regulators with therapeutic potential to alleviate RyR2 Ca leak. In our academic work at UMN, we have a funded R01 grant to apply this technology to studying RyR2 function and therapy in the heart; PP has obtained an exclusive commercial license for this UMN patent. In this project, we will apply this technology for therapeutic discovery to correct intracellular Ca signaling in Alzheimer’s disease. In Phase I, we will establish a screening funnel for (a) a large-scale HTS campaign and (b) subsequent lead development via structure-activity relationship (SAR) studies. In Phase II, we will expand SAR, and begin cell-based and animal studies using models of AD. To achieve the objectives in Phase I, PP (1) has demonstrated experience applying this FRET system for RyR2-targeted HTS, (2) will use its proprietary high-precision, high-throughput FLT plate reader (FLT-PR), (3) has functionally validated Hits yielded by this HTS platform, and (4) has identified leak inhibitors of RyR2 in heart. The Phase I Specific Aims: Aim 1 – Primary HTS of a 50,000-compound CNS-selected library, to identify compounds that correct the leaky RyR state. Aim 2 – Determine functional effects of Hits from Aim 1. We have assembled an outstanding interdisciplinary team, including academic experts from several universities (medicinal chemist Aldrich at UMN; RyR2 AD expert Stutzmann at Rosalind Franklin University, human RyR2 expert Zima at Loyola University Chicago, complementing the Photonic team’s expertise on AD-targeted HTS. These collaborations, and our track record of successful collaboration with a major drug company, combine to ensure the successful future commercialization of this project.

项目摘要 Photonic Pharma LLC（PP）提出第一阶段SBIR项目，以启动高通量筛选（HTS）， 发现病理性渗漏的兰尼碱受体（RyR）钙（Ca）的小分子变构抑制剂 释放通道，以阻止或逆转与年龄相关的神经退行性疾病，重点是阿尔茨海默病 （AD）。在AD中，失调的细胞内钙燃料的病理生理恶性循环。RyR负责 从细胞内储存细胞器（肌浆网- SR;内质网）触发Ca释放 - ER）。由此产生的Ca信号传导对于肌肉和非肌肉细胞中的许多细胞过程是必不可少的。 RyR功能失调，产生静息ER/SR的Ca-渗漏状态，已被确定为 与年龄相关的疾病，特别是AD。在这个提议中，我们针对RyR 2， 同种型，其已被明确鉴定为AD发病机制和治疗的靶标。我们有 将我们在UMN的学术研究转化为靶向RyR 2的基于荧光的HTS结构分析 (US专利10，281，476）。该FRET测定使用荧光标记的RyR 2调节剂、钙调蛋白（CaM）和钙调蛋白（CaM）。 FKBP 12.6（FKBP），以监测RyR 2-CaM结合。使用小型试验屏幕，我们已经演示了 化合物对我们的FRET读数的影响与静息RyR 2活性（Ca泄漏）之间的负相关。这 建立了HTS平台，以确定具有治疗潜力的变构调节剂，以减轻RyR 2 Ca 漏水在我们在UMN的学术工作中，我们有一个R 01资助基金来应用这项技术来研究RyR 2 PP已获得该UMN专利的独家商业许可。在这 项目，我们将应用这项技术的治疗发现，以纠正细胞内钙信号， 老年痴呆症在第一阶段，我们将建立一个筛选漏斗，用于：（a）大规模的HTS活动 和（B）通过结构-活性关系（SAR）研究的后续先导物开发。在第二阶段，我们将 扩大SAR，并开始使用AD模型进行基于细胞的研究和动物研究。实现阶段目标 我，PP（1）已经证明了将这种FRET系统应用于RyR 2靶向HTS的经验，（2）将使用其 专有的高精度、高通量FLT酶标仪（FLT-PR），（3）具有经功能验证的Hits （4）已经鉴定了心脏中RyR 2的泄漏抑制剂。第一阶段的具体目标： 目标1 - 50，000种化合物CNS选择文库的初级HTS，以鉴定校正CNS选择文库的化合物。 Leaky RyR态目标2 -确定目标1命中的功能效果。我们制定了一份 优秀的跨学科团队，包括来自多所大学的学术专家（药物化学家 奥尔德里奇在UMN; RyR 2 AD专家Stutzmann在罗莎琳德富兰克林大学，人类RyR 2专家Zima在 洛约拉大学芝加哥，补充光子团队的专业知识，对广告为目标的HTS。这些 合作，以及我们与一家大型制药公司成功合作的记录，联合收割机结合起来， 确保该项目未来的成功商业化。