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.

项目总结